WO2009049028A1 - Pyrrolopyrimidine compounds and their use as janus kinase modulators - Google Patents

Abstract

Provided herein are pyrrolopyrimidine compounds of Formula (I) wherein R1 is a heteroaryl containing at least one S atom, and optionally substituted on a ring carbon by one, two, or three substituents each independently selected from the group consisting of : halo, hydroxyl, nitro, formyl, formamido, cyano, sulfonyl, carboxy, amino, amido, acylamino, carbamoyl, sulphamoyl, alkyl, alkenyl, CF3, ureido, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, carbaldehyde oxime, N -alkylsulphamoyl, N-alkylcarbamoyl, -OR13R11 or -R13R11; R2 is phenyl or pyridinyl, wherein R2 optionally substituted on a ring carbon by one, two, or three substituents each indenpendently selected from the group consisting of : halo, hydroxyl, cyano, nitro, formyl, formamido, carboxy, sulfonyl, amino, amido, -N- alkyl -amino, carbamoyl, sulphamoyl, CF3, ureido, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, N-alkylcarbamoyl, -OR11, -OR12R11, or -R12R11; and methods of making and using the same. Such compounds may be used in inflammatory or myeloproliferative disorders. The disclosure also provides for treating cancer.

Description

PIRROLOPYRIMIDINE COMPOUNDS AND THEIR USE AS JANUS KINASE MODULATORS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 60/978,562, filed October 9, 2007, and to U.S. Provisional Application No. 61/041,997, filed April 3, 2008, the entire contents of which are incorporated herein by reference.

BACKGROUND

[0002] Protein kinases are enzymes that play key roles in signaling pathways since they catalyze the phosphorylation of specific residues leading to the transduction of extra and intra cellular signals, including the action of cytokines on their receptors, growth factors, communication with the nuclei and the triggering of various biological events. In normal cellular physiology, cell cycle control, cell growth, differentiation, apoptosis, mobility, mitogenesis, and various other structural and functional events appear to be mediated by kinases.

[0003] Aberrant kinase activity has been implicated in many diseases including cancers, in immunological and auto-immune disorders, in inflammatory disorders, in diabetes, fibrosis of the liver and kidney, atherosclerosis and in ocular diseases. Inhibition of such kinase activity may be beneficial in e.g., the treatment of such diseases.

[0004] The Janus kinases (JAKs) are cellular kinases and consist of four members - JAKl, JAK2, JAK3 and TYK2. The JAKs may play a crucial role in regulating cell behavior induced by a number of cytokines. As such, compounds which modulate the activity of the JAKs have potential utility in several indications driven by a dysregulation of signaling pathways normally associated with cytokine regulation. This includes immune and inflammatory diseases in which dysregulated cytokine pathways are thought to play a role. In addition, somatic mutations in the hematopoietic system leading to activation of the JAK pathway has been linked to the myeloproliferative disorders, of cell proliferation and in several cells related to several kinds of immune function. Through the angiogenic role of JAK2 downstream of EPO receptors, JAK kinases have been implicated in ocular diseases such as Age Related Macular Degeneration (AMD), diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR).

[0005] Accordingly, there is a need to develop compounds useful as modulators of kinases, particularly, JAK kinase, given the inadequate treatments available for the aforementioned diseases where the JAK signaling pathway is dysregulated, or recruited directly or indirectly.

SUMMARY

[0006] Provided herein are novel compounds that may inhibit and/or modulate JAK, for example, JAK2. In some embodiments, the disclosed compounds may inhibit or modulate one or more of the JAK family, e.g, JAKl, JAK2, JAK3, and/or TYK2, and/or may inhibit or modulate KDR. Treatment or amelioration of disease states and pathological conditions that implicate JAK, e.g. JAK2, pathways are contemplated herein, and such treatment comprises administering one or more of the disclosed compounds, such as those recited in Formulas I, II, or III, or administering a composition as described herein comprising a disclosed compound. For example, disclosed compounds may have an IC₅₀ against a JAK of less than about 500 nM.

[0007] Also contemplated herein are methods of treating myeloproliferative disorders such as polycythemia vera, myelofibrosis, and essential thrombocythemia by administering disclosed compounds. Additionally, methods of treating afflictions such as cancer and/or inflammation are contemplated.

DETAILED DESCRIPTION

[0008] The present disclosure is directed in part towards novel compounds and compositions that modulate or inhibit pathways that signal through JAK and methods of making and using the same.

[0009] In some embodiments, the disclosed compounds may inhibit or modulate one or more of the JAK family, e.g, JAKl, JAK2, JAK3, and/or TYK2, and/or may inhibit or modulate KDR. [0010] Before further description of the present invention, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and understood as by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.

[0011] The term "therapeutic agent" is art-recognized and refers to any chemical moiety that is a biologically, physiologically, or pharmacologically active substance that acts locally or systemically in a subject. Examples of therapeutic agents, also referred to as "drugs", are described in well-known literature references such as the Merck Index, the Physicians Desk Reference, and The Pharmacological Basis of Therapeutics, and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances which affect the structure or function of the body; or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment.

[0012] The term "therapeutic effect" is art- recognized and refers to a local or systemic effect in animals, particularly mammals, and more particularly humans caused by a pharmacologically active substance. The term thus means any substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease or in the enhancement of desirable physical or mental development and/or conditions in an animal or human. The phrase "therapeutically-effective amount" means that amount of such a substance that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment. The therapeutically effective amount of such substance will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. For example, certain compositions of the present invention may be administered in a sufficient amount to produce some desired local or systemic effect at a reasonable benefit/risk ratio applicable to such treatment.

[0013] The term "modulation" is art-recognized and refers to up regulation (i.e., activation or stimulation), down regulation (i.e., inhibition or suppression) of a response, or the two in combination or apart. [0014] A "patient," "subject" or "host" to be treated by the subject method may mean either a human or non-human animal.

[0015] The term "treating" is art-recognized and refers to curing as well as ameliorating at least one symptom of any condition or disease.

[0016] The term "prodrug" is art-recognized and is intended to encompass compounds which, under physiological conditions, are converted into the agents of the present invention. A common method for making a prodrug is to select moieties which are hydrolyzed under physiological conditions to provide the desired compound. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal or the target organ or cell.

[0017] The term "alkyl" is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C₁-C₃O for straight chain, C3-C30 for branched chain), and alternatively, about 20 or fewer, e.g. from 1 to 6 carbons. Likewise, cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure. The term "alkyl" is also defined to include halosubstituted alkyls.

[0018] Moreover, the term "alkyl" (or "lower alkyl") includes "substituted alkyls", which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain may themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls may be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl- substituted alkyls, -CN, and the like.

[0019] The term "aralkyl" is art-recognized and refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group). The term alkanoyl refers to an alkyl group as defined above attached through a carbonyl bridge.

[0020] The terms "alkenyl" and "alkynyl" are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively. The term "alkylene" refers to an organic radical formed from an unsaturated aliphatic hydrocarbon and can include substituted alkylenes using the substituents noted above; "alkenylene" denotes an acyclic carbon chain which includes a carbon-to-carbon double bond and can include substituted alkylenes using the substituents noted above.

[0021] Unless the number of carbons is otherwise specified, "lower alkyl" refers to an alkyl group, as defined above, but having from one to about ten carbons, alternatively from one to about six carbon atoms in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths.

[0022] 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.

[0023] The term "aryl" as used herein refers to a mono-, bi-, or other multi-carbocyclic, aromatic ring system. The aromatic ring may be substituted at one or more ring positions with such substituents as described above, for example, 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, -CF₃, -CN, 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 aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, and/or aryls. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.

[0024] The terms ortho, meta and para are art-recognized and refer to 1,2-, 1,3- and 1,4- disubstituted benzenes, respectively. For example, the names 1,2-dimethylbenzene and ortho- dimethylbenzene are synonymous.

[0025] The terms "heteroaryl" or "heteroaromatics" are art-recognized and refer to a 5-15 membered mono-, bi-, or other multi-cyclic, aromatic ring system containing one or more heteroatoms, for example one to four heteroatoms, such as nitrogen, oxygen, and sulfur. Heteroaryls can also be fused to non-aromatic rings. The heteroaryl ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF₃, -CN, or the like. Illustrative examples of heteroaryl groups include, but are not limited to, acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furazanyl, furyl, imidazolyl, indazolyl, indolizinyl, indolyl, isobenzofuryl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyrazyl, pyridazinyl, pyridinyl, pyrimidilyl, pyrimidyl, pyrrolyl, quinolinyl, quinolizinyl, quinoxalinyl, quinoxaloyl, quinazolinyl, tetrazolyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiophenyl, triazinyl, (1,2,3,)- and (l,2,4)-triazolyl, and the like. Exemplary heteroaryl groups include, but are not limited to, a monocyclic aromatic ring, wherein the ring comprises 2 to 5 carbon atoms and 1 to 3 heteroatoms.

[0026] The terms "heterocyclyl" or "heterocyclic group" are art-recognized and refer to saturated or partially unsaturated 3- to 10-membered ring structures, alternatively 3- to 7- membered rings, whose ring structures include one to four heteroatoms, such as nitrogen, oxygen, and sulfur. Heterocycles may also be mono-, bi-, or other multi-cyclic ring systems. A heterocycle may be fused to one or more aryl, partially unsaturated, or saturated rings. Heterocyclyl groups include, for example, biotinyl, chromenyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, homopiperidinyl, imidazolidinyl, isoquinolyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxolanyl, oxazolidinyl, phenoxanthenyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl, thiazolidinyl, thiolanyl, thiomoφholinyl, thiopyranyl, xanthenyl, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF₃, -CN, or the like.

[0027] The term "heterocycloalkyl" is art-recognized and refers to a saturated heterocyclyl group as defined above.

[0028] The terms "polycyclyl" or "polycyclic group" are art- recognized and refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings. Each of the rings of the polycycle may be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, - CN, or the like.

[0029] The term "carbocycle" is art-recognized and refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.

[0030] The term "nitro" is art-recognized and refers to -NO2; the term "halogen" is art- recognized and refers to -F, -Cl, -Br or -I; the term "sulfhydryl" is art-recognized and refers to -SH; the term "hydroxyl" means -OH; and the term "sulfonyl" is art-recognized and refers to - SO2-. [0031] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:

R50 R50 I

/ I + N N R53

^R51 R52

wherein R50, R51 and R52 each independently represent a hydrogen, an alkyl, an alkenyl, - (CH2)m-R61, or R50 and R51, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. In certain embodiments, only one of R50 or R51 may be a carbonyl, e.g., R50, R51 and the nitrogen together do not form an imide. In other embodiments, R50 and R51 (and optionally R52) each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH2)m- R61. Thus, the term "alkylamine" includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R50 and R51 is an alkyl group.

[0032] The term "amido" is art recognized as an amino- substituted carbonyl and includes a moiety that may be represented by the general formula:

wherein R50 and R51 are as defined above. Certain embodiments of the amide in the present invention will not include imides which may be unstable.

[0033] The term "acylamino" is art-recognized and refers to a moiety that may be represented by the general formula: O

-N- -R54

R50

wherein R50 is as defined above, and R54 represents a hydrogen, an alkyl, an alkenyl or - (CH₂)_m-R61, where m and R61 are as defined above.

[0034] The term "alkylthio" refers to an alkyl group, as defined above, having a sulfur radical attached thereto. In certain embodiments, the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH2)m-R61, wherein m and R61 are defined above. Representative alkylthio groups include methylthio, ethylthio, and the like.

[0035] The term "carbonyl" is art recognized and includes such moieties as may be represented by the general formulas:

wherein X50 is a bond or represents an oxygen or a sulfur, and R55 and R56 represents a hydrogen, an alkyl, an alkenyl, -(CH₂)_m-R61or a pharmaceutically acceptable salt, R56 represents a hydrogen, an alkyl, an alkenyl or -(CH₂)_m-R61, where m and R61 are defined above. Where X50 is an oxygen and R55 or R56 is not hydrogen, the formula represents an "ester". Where X50 is an oxygen, and R55 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R55 is a hydrogen, the formula represents a "carboxylic acid". Where X50 is an oxygen, and R56 is hydrogen, the formula represents a "formate". In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a "thiolcarbonyl" group. Where X50 is a sulfur and R55 or R56 is not hydrogen, the formula represents a "thiolester." Where X50 is a sulfur and R55 is hydrogen, the formula represents a "thiolcarboxylic acid." Where X50 is a sulfur and R56 is hydrogen, the formula represents a "thiolformate." On the other hand, where X50 is a bond, and R55 is not hydrogen, the above formula represents a "ketone" group. Where X50 is a bond, and R55 is hydrogen, the above formula represents an "aldehyde" group. [0036] The term "sulfonamido" is art recognized and includes a moiety that may be represented by the general formula:

O

N S OR56

R50 O in which R50 and R56 are as defined above.

[0037] The term "sulfamoyl" is art-recognized and refers to a moiety that may be represented by the general formula:

in which R50 and R51 are as defined above.

[0038] The term "sulfonyl" is art-recognized and refers to a moiety that may be represented by the general formula:

in which R58 is one of the following: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

[0039] The definition of each expression, e.g. alkyl, m, n, and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

[0040] Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, polymers 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, diastereomers, (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.

[0041] 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.

[0042] 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, cyclization, elimination, or other reaction.

[0043] 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.

[0044] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67^th Ed., 1986-87, inside cover. Also for purposes of this invention, the term "hydrocarbon" is contemplated to include all permissible compounds having at least one hydrogen and one carbon atom. In a broad aspect, the permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds that may be substituted or unsubstituted.

[0045] The term "pharmaceutically- acceptable salts" is art-recognized and refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds, including, for example, those contained in compositions of the present invention.

[0046] The term "pharmaceutically acceptable carrier" is art-recognized and refers to a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the subject composition and its components and not injurious to the patient. Some examples of materials which may serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0047] The terms "systemic administration," "administered systemically," "peripheral administration" and "administered peripherally" are art-recognized and refer to the administration of a subject composition, therapeutic or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration. [0048] The term "ocular administration" refers to the administration of a subject composition, therapeutic or other material on or into the eye, including topical and parenteral administration.

[0049] "Inhalation administration" or "administered by inhalation" refers to administration of a subject composition, therapeutic or other material by a pulmonary route, e.g. aerosol inhalation or nasal administration.

[0050] The terms "parenteral administration" and "administered parenterally" are art- recognized and refer to modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articulare, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

Compounds

[0051] Provided herein, in part, is a compound according to formula I:

I

[0052] In general, R₁ of Formula I is a heteroaryl, for example, a heteroaryl containing at least one sulfur (S) atom, where the heteraryl can be optionally substituted on a ring carbon by one, two, or three substituents each independently selected from the group consisting of: halo, hydroxyl, nitro, formyl, formamido, cyano, carboxy, amino, amido, acylamino, carbamoyl, sulphamoyl, alkyl, alkenyl, CF₃, ureido, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, carbaldehyde oxime, N-alkylsulphamoyl, N-alkylcarbamoyl, -0-R₁₃R₁₁ or -R₁₃R₁₁. R₁ can be selected, in some embodiments, from the group consisting of: optionally substituted: furanyl, thienyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, furazanyl, triazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, quinolyl, benzimidazolyl, benzothiophene, or thienopyridine. For example, R₁ may be an optionally substituted monocyclic or bicyclic heteroaryl, e.g. an optionally substituted thienyl, or optionally substituted benzothiophene. Formula (I), as pictorially depicted above, includes a pyrrolopyrimidine core. In some embodiments, the substituent of R₁ at the ortho position relative to the pyrrolopyrimidine core is H.

[0053] R₂ may be a heteroaryl, e.g. a phenyl or pyridinyl, wherein R₂ can be optionally substituted on a ring carbon by one, two, or three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, nitro, formyl, formamido, carboxy, amino, amido, -N-alkyl-amino, carbamoyl, sulphamoyl, CF₃, ureido, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, -N-alkyl-amino-N-alkylcarbamoyl, - OR₁₁, -OR₁₂R₁₁, or -R₁₂R₁₁. In some embodiments, R₂ may be substituted with only one moiety other than H. In other embodiments, R₂ may be para or meta to the nitrogen attachment.

[0054] R₁₁ can be independently selected from the group consisting of: aryl, heteroaryl, cycloalkyl and heterocycloalkyl, wherein R₁₁ can be optionally substituted by one to four substituents each independently selected from the group consisting of: halo, cyano, alkyl, carbonyl, hydroxyl, alkyl-hydroxyl, nitro, formyl, formamido, carboxy, amino, amido, CF₃, ureido, carbamoyl, sulphamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N- alkylsulphamoyl, N-alkylcarbamoyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl.

[0055] In some embodiments, R₁₂ is alkylene, -SO₂-, -SO₂N-alkylene-, or a bond. R₁₃ may be alkylene, alkenylene, -C(O)-, -SO₂-, or a bond.

[0056] In an exemplary embodiment, R₁ of formula I may be represented by:

where, for example, R₃ and R₄ may each be independently selected from the group consisting of: hydrogen, halo, hydroxyl, nitro, formyl, formamido, carboxy, amino, amido, acylamino, carbamoyl, sulphamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N- alkylsulphamoyl, N-alkylcarbamoyl, aryl, heterocycle, cycloalkyl, -OR₁₃, -OR₁₃R₁₁, or - R₁₃R₁₁, or R₃ and R₄ taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic or heterocyclic ring, optionally substituted by one to four substituents each independently selected from the group consisting of: halo, cyano, alkyl, carbonyl, hydroxyl, nitro, formyl, formamido, carboxy, amino, carbamoyl, sulphamoyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, N-alkylcarbamoyl. R' ₃ may be selected from hydrogen, halo, hydroxyl or alkyl.

[0057] In some embodiments, R₁ of Formual I may be represented as:

wherein for each occurrence, R₅ are each independently selected from the group consisting of: H, halo, acylamino, alkanoyl, carbaldehyde oxime,or alkyl. For example, in some embodiments, at least one R₅ is methyl. In other embodiments, R₅ for one occurrence is methyl, and the remainder of the R₅ moities may be H. In other embodiments, one or more R₅ moieties is a substituted alkyl, e.g., substituted by one or more hydroxyl or halo moieties.

[0058] In an embodiment R₂ can be represented as:

wherein: X is N or CR₆; R₆ is H or alkyl, R₇ and Rg, independently for each occurrence, is chosen from the group consisting of: H, heterocycle, -O-heterocycle, -alkylene-heterocycle, - O-alkylene-heterocycle, -SC^N-alkylene-heterocycle, or -Sθ₂-heterocycle, wherein said heterocycle is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, alkyl, carbonyl, hydroxyl, nitro, formyl, formamido, carboxy, amino, amido, acylamino, carbamoyl, sulphamoyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, and N-alkylcarbamoyl. For example, R₈ may include a heterocycle substituted with methyl. In an exemplary embodiment, Rg is H. [0059] For example, Rg may be H and R₇ may be an optionally substituted heterocycle, or - O-alkylene-heterocycle, wherein heterocycle may be chosen from the group consisting of: pyrrolidinyl, piperazinyl, or morpholinyl. In a different exemplary embodiment, R₈ may be H and R₇ may be selected from the group consisting of: methylpiperazine, piperazine, -CH₂- piperdine, -CH₂-methylimidazole, -CH₂-morpholine, imidazole, and 2-pyrrolidin-lylethoxy.

[0060] In an embodiment, this disclosure also provides for a compound of Formula I which inhibits JAK2 with an IC₅₀ at least about ten times lower as compared to a compound represented by Formula A:

wherein R₁ and R₂ are defined above. For example, compound B has a IC₅₀ against JAK2 of 384 nM, whereas compound C has an IC₅₀ against JAK2 >30000 nM.

[0061] In particular embodiment when R₁ is thiophene, with attachment to the pyrimidine at the 2-position, the 3-position on the thiophene is hydrogen. For example, a methyl at this position may result in a loss of JAK2 activity.

[0062] In an aspect of the invention, a disclosed compound is represented by formula II:

II wherein R₃ and R₄ may each be independently selected from the group consisting of: hydrogen, halo, hydroxyl, cyano, nitro, formyl, formamido, carboxy, amino, amido, acylamino, carbaldehyde oxime, carbamoyl, sulphamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, N-alkylcarbamoyl, or -R₁₃R₁₁, or R₃ and R₄ taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic or heterocyclic ring, optionally substituted by one to four substituents each independently selected from the group consisting of: halo, alkyl, carbonyl, hydroxyl, nitro, formyl, formamido, carboxy, amino, amido, carbamoyl, sulphamoyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, N-alkylcarbamoyl. For example, R₃ and R₄ are each independently selected from H, methyl, or ethyl, e.g. R₃ may be H or methyl and R₄ may be H or methyl.

[0063] In other exemplary embodiments, R₃ or R₄ can be chosen from:

wherein R₁₆ is chosen from the group consisting of: H, alkyl, alkoxy, halo, -SCh-heterocycle, and N-alkyl sulphamoyl.

[0064] X may be N or CR₆, where R₆ is H or alkyl.

[0065] R₇ or Rg can chosen from the group consisting of: H, heterocycle, -O-alkyl, -O- heterocycle, -O-alkylene-heterocycle, -SOiN-heterocycle, -Sθ₂-heterocycle, -C(O)- heterocycle, -C(O)-NH-alkyl-C(O)OH, -alkylene-heterocycle, or -N-alkylene-amino, wherein said heterocycle is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, cyano, alkyl, carbonyl, hydroxyl, nitro, formyl, formamido, carboxy, amino, amido, carbamoyl, sulphamoyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, and N-alkylcarbamoyl. In some embodiments, at least one Rg is H. The heterocycle can be chosen, for example, from pyrrolidinyl, piperazinyl, morpholinyl, piperdine, pyridinyl, imidazoyl, and triazoyl. [0066] R₁₁ can independently selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, wherein R₁₁ can be optionally substituted by one to four substituents each independently selected from the group consisting of: halo, alkyl, carbonyl, of halo, hydroxyl, nitro, formyl, formamido, carboxy, amino, amido, carbamoyl, sulphamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, N-alkylcarbamoyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl and R₁₃ can be alkylene, alkenylene, -C(O)-, or a bond. Pharmaceutically acceptable salts, prodrugs, N-oxides, and hydrates thereof of Formula II are contemplated.

[0067] In an embodiment, compounds of Formula II can be represented by Formula III:

Ilia or IHb

wherein R₉, independently for each occurrence, is chosen from the group consisting of: H, cyano, methyl, ethyl or -C(O)-alkyl -C(O)-heterocycle, or -heterocycle;

R₁₉, independently for each occurrence, chosen from H or halo; and

Rg_a, independently for each occurrence, is chosen from the group consisting of: H, alkyl, amido, -N-alkyl-sulfamoyl, sulfonyl, alkanoyl, carbamoyl, -C(0)-alkyl-NR2oR2o, -C(O)- heterocycle, and heterocycle, wherein R₂o is independently selected from H and alkyl.

[0068] In some embodiments, R₇ or Rg of Formula II or Ilia or IHb can selected from the group consisting of:

and , wherein R_1S is alkyl or alkanoyl. [0069] In another embodiment, Rg_a is chosen from:

, and

[0070] Also contemplated herein are the compounds: N-(4-(4-methylpiperazin-l- yl)phenyl)-4-(4-methylthiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 4-[4-(4-Methyl- thiophen-2-yl)-7H-pyrrolo[2,3-<i]pyrimidin-2-ylamino]-N-(2-pyrrolidin-l-yl-ethyl)- benzenesulfonamide, [4-(4-Methyl-piperazin-l-yl)-phenyl]-[4-(5-methyl-thiophen-2-yl)-7H- pyrrolo[2,3-<i]pyrimidin-2-yl]-amine, [4-(5-Chloro-thiophen-2-yl)-7H-pyrrolo[2,3- J]pyrimidin-2-yl] - [4-(2-pyrrolidin- 1 -yl-ethoxy)-phenyl] -amine, (5- { 2- [4-(2-Pyrrolidin- 1 -yl- ethoxy)-phenylamino]-7H-pyrrolo[2,3-(i]pyrimidin-4-yl}-thiophen-2-yl)-methanol, A-(A- Methylthiophen-2-yl)-N-(4-(pyridin-4-ylmethyl)phenyl)-7H-pyrrolo[2,3-(i]pyrimidin-2-amine, N-(4-((lH-l,2,4-Triazol-l-yl)methyl)phenyl)-4-(4-methylthiophen-2-yl)-7H-pyrrolo[2,3- J]pyrimidin-2-amine, 4-(4-Methylthiophen-2-yl)-N-(4-(pyridin-3-yl)phenyl)-7H-pyrrolo[2,3- J]pyrimidin-2-amine, 4-(4-Methylthiophen-2-yl)-N-(4-(piperidin-4-yloxy)phenyl)-7H- pyrrolo[2,3-J]pyrimidin-2-amine, 4-(4-Methylthiophen-2-yl)-N-(4-(piperidin-l- ylmethyl)phenyl)-7H-pyrrolo[2,3-(i]pyrimidin-2-amine, (5-(2-(4-(4-Methylpiperazin-l- yl)phenylamino)-7H-pyrrolo[2,3-(i]pyrimidin-4-yl)thiophen-2-yl)methanol, 5-(2-(4- Morpholinophenylamino)-7H-pyrrolo[2,3-(i]pyrimidin-4-yl)thiophene-2-carboxamide, [4-(5- Methyl-thiophen-2-yl)-7H-pyrrolo[2,3-(i]pyrimidin-2-yl]-[4-(piperidine-4-sulfonyl)-phenyl]- amine, [4-(4-Methyl-thiophen-2-yl)-7H-pyrrolo[2,3-<i]pyrimidin-2-yl]-(3-pyrrolidin-l- ylmethyl-phenyl)-amine, [4-(4-Methyl-thiophen-2-yl)-7H-pyrrolo[2,3-J]pyrimidin-2-yl]-(3- morpholin-4-ylmethyl-phenyl)-amine, 4-(4-Methylthiophen-2-yl)-N-[4-(morpholin-4- ylmethyl)phenyl] -7H-pyrrolo[2,3-<i]pyrimidin-2-amine, N- { A- [(2-Methyl- lH-imidazol- 1 - yl)methyl]phenyl}-4-(4-methylthiophen-2-yl)-7H-pyrrolo[2,3-(i]pyrimidin-2-amine, 4-(4- Methylthiophen-2-yl)-N-[4-(2-morpholin-4-ylethyl)phenyl]-7H-pyrrolo[2,3-(i]pyrimidin-2- amine, N-(6-(4-Methylpiperazin-l-yl)pyridin-3-yl)-4-(4-methylthiophen-2-yl)-7H-pyrrolo[2,3- J]pyrimidin-2-amine, N-[4-(lH-Imidazol-l-yl)phenyl]-4-(4-methylthiophen-2-yl)-7H- pyrrolo[2,3-(i]pyrimidin-2-amine, N-(4-Methoxyphenyl)-4-(thiophen-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-amine, N-(4-(2-(Pyrrolidin-l-yl)ethoxy)phenyl)-4-(thiophen-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine, N-(3-Morpholinopropyl)-4-(thiophen-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-amine, 2-(4-Methoxyphenoxy)-4-(thiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidine, 5-(5-{2-[4-(2-Pyrrolidin-l-yl-ethoxy)-phenylamino]-7H-pyrrolo[2,3-(i]pyrimidin-4-yl}- thiophen-2-ylmethylene)-thiazolidine-2,4-dione, (Z)-5-((5-(2-(4-(4-Methylpiperazin-l- yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)thiophen-2-yl)methylene)thiazolidine-2,4- dione, 5-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-<i]pyrimidin-4- yl)thiophene-2-carbonitrile, (5-(2-(4-(4-methylpiperazin-l-yl)phenylamino)-7Η-pyrrolo[2,3- d]pyrimidin-4-yl)thiophen-2-yl)(morpholino)methanone, [4-(5-Methyl-benzo[b]thiophen-2- yl)-7H-pyrrolo[2,3-<i]pyrimidin-2-yl]-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-amine, [4-(5- Methyl-benzo[b]thiophen-2-yl)-7H-pyrrolo[2,3-(i]pyrimidin-2-yl]-[4-(4-methyl-piperazin-l- ylmethyl) -phenyl] - amine, 4- (B enzo [b] thiophen-2-yl) -N- (4- (4-methylpiperazin- 1 -yl)phenyl) - 7H-pyrrolo[2,3-J]pyrimidin-2-amine , 4-(Benzo[b]thiophen-2-yl)-N-(6-(4-methylpiperazin- 1- yl)pyridin-3-yl)-7H-pyrrolo-[2,3-(i]pyrimidin-2-amine, N-(4-(2-(Pyrrolidin-l- yl)ethoxy)phenyl)-4-(benzo[b]thiophen-2-yl)-7H-pyrrolo[2,3-<i]pyrimidin-2-amine, and pharmaceutically acceptable salts, prodrugs, N-oxides, and hydrates thereof.

[0071] Further compounds contemplated herein include:

or pharmaceutically acceptable salts, prodrugs, N-oxides, and hydrates thereof.

[0072] Also provided herein are compounds chosen from the group consisting of:

[4-(4-Methyl-thiophen-2-yl)-7H-pyrrolo[2,3-<i]pyrimidin-2-yl]-[4-(2-pyrrolidin-l-yl-ethoxy)- phenyl] -amine;

[4-(5-Methyl-thiophen-2-yl)-7H-pyrrolo[2,3-J]pyrimidin-2-yl]-[4-(2-pyrrolidin-l-yl-ethoxy)- phenyl] -amine;

{4-[5-(3,5-Dimethyl-isoxazol-4-yl)-thiophen-2-yl]-7H-pyrrolo[2,3-J]pyrimidin-2-yl}-[4-(2- pyrrolidin- 1 -yl-ethoxy)-phenyl] -amine;

2- { 2- [4-(2-Pyrrolidin- 1 -yl-ethoxy)-phenylamino] -7H-pyrrolo [2,3-<i]pyrimidin-4-yl } - benzo[b]thiophene-6-carbonitrile;

{4-[5-(3,5-Dimethyl-isoxazol-4-yl)-thiophen-2-yl]-7H-pyrrolo[2,3-J]pyrimidin-2-yl}-[4-(2- methyl-imidazol- 1 -ylmethyl)-phenyl] -amine; 2- { 2-[4-(2-Methyl-imidazol- 1 -ylmethyl)-phenylamino] -7H-pyrrolo[2,3-^]pyrimidin-4-yl } - benzo [b] thiophene- 6-carbonitrile ;

{4-[5-(3-Isopropoxy-phenyl)-thiophen-2-yl]-7H-pyrrolo[2,3-<i]pyrimidin-2-yl}-[4-(2- pyrrolidin- 1 -yl-ethoxy)-phenyl] -amine;

N-fert-Butyl-3-(5-{2-[4-(2-methyl-imidazol-l-ylmethyl)-phenylamino]-7H-pyrrolo[2,3- J]pyrimidin-4-yl } -thiophen-2-yl)-benzenesulfonamide;

{4-[5-(2,3-Dihydro-benzo[l,4]dioxin-6-yl]-thiophen-2-yl]-7Η-pyrrolo[2,3-d]pyrimidin-2-yl}-4-(2- methyl-imidazol-imidazol- 1 -ylmethyl)-phenyl] -amine ;

{4-[5-(3-Isopropoxy-phenyl)-thiophen-2-yl]-7H-pyrrolo[2,3-(i]pyrimidin-2-yl}-[4-(2-methyl- imidazol- l-ylmethyl)-phenyl] -amine;

(2-{2-[3-(4-Methyl-piperazin-l-yl)-phenylamino]-7Η-pyrrolo[2,3-d]pyrimidin-4-yl}- benzo[b]thiophen-5-yl)-moφholin-4-yl-methanone;

[3-(4-Methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-[4-(4-methyl-thiophen-2-yl)-7H- pyrrolo[2,3-_<i]pyrimidin-2-yl]-amine;

4-(4-Methylthiophen-2-yl)-N-(4-(l-moφholinoethyl)phenyl)-7H-pyrrolo[2,3-^]pyrimidin-2- amine hydrochloride;

N-(4-(2-Methyl-lΗ-imidazol-l-yl)phenyl)-4-(4-methylthiophen-2-yl)-7Η-pyrrolo[2,3- d] pyrimidin-2- amine hydrochloride ;

2-(4-(4-(4-Methylthiophen-2-yl)-7H-pyrrolo[2,3-(i]pyrimidin-2-ylamino)benzamido)acetic acid;

4-(4-Methylthiophen-2-yl)-N-(4-(pyrrolidin-l-ylmethyl)phenyl)-7H-pyrrolo[2,3-(i]pyrimidin-

2-amine;

5-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-^]pyrimidin-4-yl)thiophene-2- carboxamide;

2-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-^]pyrimidin-4- yl)benzo[b]thiophene-7-carbonitrile;

2-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)benzo[b]thiophene-4-carbonitrile; 5-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-(i]pyrimidin-4-yl)-3- methylthiophene-2-carbonitrile;

5-(2-(4-(2-(Pyrrolidin-l-yl)ethoxy)phenylamino)-7H-pyrrolo[2,3-(i]pyrimidin-4-yl)-3- methylthiophene-2-carbonitrile;

2-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-(i]pyrimidin-4-yl)thiophene-3- carbonitrile;

2-(2-(3-(4-Methylpiperazin-l-yl)phenylamino)-7Η-pyrrolo[2,3-d]pyrimidin-4-yl)thiophene-3- carbonitrile;

4-(5-(3,5-Dimethylisoxazol-4-yl)thiophen-2-yl)-N-(4-(moφholinomethyl)phenyl)-7H- pyrrolo[2,3-_<i]pyrimidin-2-amine;

4-(Benzo[b]thiophen-2-yl)-N-(4-(moφholinomethyl)phenyl)-7H-pyrrolo[2,3-<i]pyrimidin-2- amine hydrochloride;

2-(2-(4-(Moφholinomethyl)phenylamino)-7H-pyrrolo[2,3-<i]pyrimidin-4- yl)benzo[b]thiophene-6-carbonitrile;

4-(5-Methylbenzo[b]thiophen-2-yl)-N-(4-(moφholinomethyl)phenyl)-7H-pyrrolo[2,3- d] pyrimidin-2- amine ;

4-(Benzo[b]thiophen-2-yl)-N-(4-((piperidin-l-yl)methyl)phenyl)-7H-pyrrolo[2,3-(i]pyrimidin- 2-amine;

4-(Benzo[b]thiophen-2-yl)-N-(4-((piperidin-l-yl)methyl)phenyl)-7H-pyrrolo[2,3-(i]pyrimidin- 2-amine;

N-fer?-Butyl-5-(2-(4-((2-methyl-lH-imidazol-l-yl)methyl)phenylamino)-7H-pyrrolo[2,3- J]pyrimidin-4-yl)thiophene-2-carboxamide;

(4-Methylpiperazin-l-yl)(3-(4-(4-methylthiophen-2-yl)-7H-pyrrolo[2,3-(i]pyrimidin-2- ylamino)phenyl)methanone;

N-fer?-Butyl-3-methyl-5-(2-(4-(2-(pyrrolidin-l-yl)ethoxy)phenylamino)-7H-pyrrolo[2,3- J]pyrimidin-4-yl)thiophene-2-carboxamide; 5-(2-(4-(lH-Imidazol-l-yl)phenylamino)-7H-pyrrolo[2,3-^]pyrimidin-4-yl)thiophene-2- carbonitrile;

4-(4-Methylthiophen-2-yl)-N-(4-((piperazin-l-yl)methyl)phenyl)-7H-pyrrolo[2,3-(i]pyrimidin- 2- amine;

l-(4-((4-(4-(4-Methylthiophen-2-yl)-7H-pyrrolo[2,3-J]pyrimidin-2- ylamino)phenyl)methyl)piperazin- 1 -yl)ethanone;

2-Methyl- 1 -(4- { 4- [4-(4-methyl-thiophen-2-yl)-7H-pyrrolo[2,3-^]pyrimidin-2-ylamino] - benzyl } -piperazin- 1 -yl)-propan- 1 -one;

4-(4-Ethylthiophen-2-yl)-N-(4-(moφholinomethyl)phenyl)-7H-pyrrolo[2,3-(i]pyrimidin-2- amine;

N-(4-(Moφholinomethyl)phenyl)-4-(4-propylthiophen-2-yl)-7H-pyrrolo[2,3-<i]pyrimidin-2- amine;

N-(3-(4-Methylpiperazin-l-yl)phenyl)-4-(4-(morpholinomethyl)thiophen-2-yl)-7H- pyrrolo[2,3-<i]pyrimidin-2-amine;

2-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-^]pyrimidin-4- yl)benzo [b] thiophene- 5 -carbonitrile ;

4-(4-((Diethylamino)methyl)thiophen-2-yl)-N-(4-(4-methylpiperazin-l-yl)phenyl)-7H- pyrrolo[2,3-_<i]pyrimidin-2-amine;

[5-(2-{ [4-(lH-Imidazol-l-yl)phenyl]amino}-7H-pyrrolo[2,3-J]pyrimidin-4-yl)-3- methylthiophen-2-yl]methanol;

[5-(2-{ [4-(lH-imidazol-l-yl)phenyl]amino}-7H-pyrrolo[2,3-J]pyrimidin-4-yl)-3- methylthiophen-2-yl] methyl acetate;

[3-Methyl-5-(2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino}-7H-pyrrolo[2,3-^]pyrimidin-4- yl)thiophen-2-yl]methanol;

{3-Methyl-5-[2-({4-[(2-methyl-lH-imidazol-l-yl)methyl]phenyl]amino}-7H-pyrrolo[2,3- J]pyrimidin-4-yl)thiophen-2-yl}methanol; N-[4-(4-Methylpiperazin-l-yl)phenyl]-4-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)-7H- pyrrolo[2,3-(i]pyrimidin-2-amine;

N-[4-(4-Methylpiperazin-l-yl)phenyl]-4-[5-(methylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2- c]pyridine-2-yl]-7H-pyrrolo[2,3-^]pyrimidin-2-amine;

4-(5-Acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)- N-[4-(4-methylpiperazin-l- yl)phenyl]-7H-pyrrolo[2,3-^]pyrimidin-2-amine;

4-[5-(2,2-Dimethylpropanoyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl]-N-[4-(4- methylpiperazin-l-yl)phenyl]-7H-pyrrolo[2,3-^]pyrimidin-2-amine;

N,N-Oiethy\-2-(2- { [4-(4-methylpiperazin- 1 -yl)phenyl] amino } -7H-pyrrolo[2,3-d]pyrimidin-4- yl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide;

N-[4-(4-Methylpiperazin-l-yl)phenyl]-4-[5-(pyridin-3-ylcarbonyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-yl]-7H-pyrrolo[2,3-^]pyrimidin-2-amine;

N-[3-(4-Methylpiperazin-l-yl)phenyl]-4-[5-(methylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2- c]pyridine-2-yl]-7H-pyrrolo[2,3-(i]pyrimidin-2-amine;

4-(5-Acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)- N-[3-(4-methylpiperazin-l- yl)phenyl]-7H-pyrrolo[2,3-(i]pyrimidin-2-amine;

4-[5-(2,2-Dimethylpropanoyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)- N-[3-(4- methylpiperazin-l-yl)phenyl]-7H-pyrrolo[2,3-(i]pyrimidin-2-amine;

Λ/,N-Diethyl-2-(2- { [3-(4-methylpiperazin- 1 -yl)phenyl] amino } -7H-pyrrolo[2,3-<i]pyrimidin-4- yl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide;

N-[3-(4-Methylpiperazin-l-yl)phenyl]-4-[5-(pyridin-3-ylcarbonyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-yl]-7H-pyrrolo[2,3-(i]pyrimidin-2-amine;

4-[5-(Cyclopropylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl]-N-[3-(4- methylpiperazin-l-yl)phenyl]-7H-pyrrolo[2,3-(i]pyrimidin-2-amine;

N-[3-(4-Methylpiperazin-l-yl)phenyl]-4-[5-(morpholin-4-ylcarbonyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-yl]-7H-pyrrolo[2,3-^]pyrimidin-2-amine; N,N-Dimethyl-2-(2-{ [3-(4-methylpiperazin-l-yl)phenyl]amino}-7H-pyrrolo[2,3-(i]pyrimidin- 4-yl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-sulfonamide;

4-{5-[(Dimethylamino)acetyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl}-N-[3-(4- methylpiperazin-l-yl)phenyl]-7H-pyrrolo[2,3-(i]pyrimidin-2-amine;

N-[3-(4-Methylpiperazin-l-yl)phenyl]-4-[5-(trifluoroacetyl)-4,5,6,7-tetrahydrothieno[3,2- c]pyridin-2-yl]-7H-pyrrolo[2,3-_<i]pyrimidin-2-amine;

4-(5-Acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-N-[4-(2-pyrrolidin-l- ylethoxy)phenyl]-7H-pyrrolo[2,3-(i]pyrimidin-2-amine;

4-[5-(Methylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl]-N-[4-(2-pyrrolidin-l- ylethoxy)phenyl]-7H-pyrrolo[2,3-_<i]pyrimidin-2-amine;

N,N-Diethy\-2-(2- { [4-(2-pyrrolidin- 1 -ylethoxy)phenyl] -amino } -7H-pyrrolo [2,3-<i]pyrimidin-4- yl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide;

N,N-Bis-(l-methylethyl)-2-(2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl]-amino}-7H-pyrrolo[2,3- J]pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide;

4-[5-(Pyridin-3-ylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl]-N-[4-(2-pyrrolidin-l- ylethoxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-2-amine;

N-fer?-Butyl-2-(2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino}-7H-pyrrolo[2,3-(i]pyrimidin-4- yl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide;

4-{5-[(5-Methylisoxazol-3-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl}-N-[4-(2- pyrrolidin-l-ylethoxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-2-amine;

4-[5-(4,6-Dimethoxy-l,3,5-triazin-2-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl]-N-[4-(2- pyrrolidin-l-ylethoxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-2-amine;

[3-(4-Methyl-piperazin-l-ylmethyl)-phenyl]-[4-(4-methyl-thiophen-2-yl)-7H-pyrrolo[2,3- d] pyrimidin-2-yl] - amine ;

[4-(4-Methyl-thiophen-2-yl)-7H-pyrrolo[2,3-<i]pyrimidin-2-yl]-(3-piperazin-l-yl-phenyl)- amine; 4-Imidazol-l-ylmethyl-phenyl)-[4-(4-methyl-thiophen-2-yl)-7H-pyrrolo[2,3-^]pyrimidin-2- yl] -amine;

[4-(4-Methyl-piperazin-l-yl)-phenyl]-[4-(4-phenyl-thiophen-2-yl)-7H-pyrrolo[2,3- J]pyrimidin-2-yl] -amine;

{4-[4-(3-Isopropyl-phenyl)-thiophen-2-yl]-7H-pyrrolo[2,3-(i]pyrimidin-2-yl}-[4-(4-methyl- piperazin-l-yl)-phenyl] -amine;

[3-(4-Methyl-piperazin-l-yl)-phenyl]-[4-(4-methyl-thiophen-2-yl)-7Η-pyrrolo[2,3- d] pyrimidin-2-yl] - amine ;

{4-[5-(3,5-Dimethyl-isoxazol-4-yl)-thiophen-2-yl]-7H-pyrrolo[2,3-J]pyrimidin-2-yl}-[3-(4- methyl-piperazin- l-yl)-phenyl] -amine;

(4-Benzo[b]thiophen-2-yl-7H-pyrrolo[2,3-(i]pyrimidin-2-yl)-[3-(4-methyl-piperazin-l-yl)- phenyl] -amine;

[4-(5-Methyl-benzo[b]thiophen-2-yl)-7Η-pyrrolo[2,3-d]pyrimidin-2-yl]-[3-(4-methyl- piperazin-l-yl)-phenyl] -amine;

2-{2-[4-(2-Methyl-imidazol-l-ylmethyl)-phenylamino]-7H-pyrrolo[2,3-J]pyrimidin-4-yl}-6,7- dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid diethylamide;

[4-(4-Ethynyl-thiophen-2-yl)-7H-pyrrolo[2,3-J]pyrimidin-2-yl]-[4-(2-methyl-imidazol-l- ylmethyl) -phenyl] - amine ;

(2- { 2-[4-(2-Methyl-imidazol- 1 -ylmethyl)-phenylamino] -7H-pyrrolo[2,3-^]pyrimidin-4-yl } - 6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-pyridin-3-yl-methanone;

N-(4-((2-methyl-lΗ-imidazol-l-yl)methyl)phenyl)-4-(5-(methylsulfonyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine;

2-{2-[4-(2-Methyl-imidazol-l-ylmethyl)-phenylamino]-7H-pyrrolo[2,3-^]pyrimidin-4-yl}-6,7- dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid ethylamide;

2-{2-[4-(2-Methyl-imidazol-l-ylmethyl)-phenylamino]-7H-pyrrolo[2,3-J]pyrimidin-4-yl}-6,7- dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid fer?-butylamide; [3-(4-Methyl-piperazine-l-sulfonyl)-phenyl]-[4-(4-methyl-thiophen-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-yl] -amine;

(5-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-(i]pyrimidin-4-yl)-3- methylthiophen-2- yl)methanol ;

3-Methyl-5-{2-[4-(methyl-piperazin-l-yl)phenylamino]-7Η-pyrrolo[2,3-d]pyrimidin-4-yl}- thiophene-2-carbaldehyde oxime;

(5-(2-(4-(Morpholinomethyl)phenylamino)-7H-pyrrolo[2,3-(i]pyrimidin-4-yl)-3 methylthiophen-2-yl)methanol;

(5-(2-(3-(Morpholinomethyl)phenylamino)-7H-pyrrolo[2,3-(i]pyrimidin-4-yl) 3- methylthiophen-2-yl)methanol;

l-(5-(2-(3-(Morpholinomethyl)phenylamino)-7H-pyrrolo[2,3-(i]pyrimidin-4-yl)-3- methylthiophen-2-yl)propan- 1 -ol;

2-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7Η-pyrrolo[2,3-d]pyrimidin-4- yl)benzo[b]thiophene-6-carbonitrile;

2-(2-(3-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-(i]pyrimidin-4- yl)benzo[b]thiophene-6-carbonitrile;

2-(2-(3-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-(i]pyrimidin-4- yl)benzo [b] thiophene- 5 -carbonitrile ;

l-(2-(2-(3-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-(i]pyrimidin-4- yl)benzo[b]thiophen-5-yl)pentan-l-one;

4-(6-(lH-Tetrazol-5-yl)benzo[b]thiophen-2-yl)-N-(4-(2-(pyrrolidin-l-yl)ethoxy)phenyl)-7H- pyrrolo[2,3-<i]pyrimidin-2-amine;

2-(2-(4-(2-(Pyrrolidin-l-yl)ethoxy)phenylamino)-7H-pyrrolo[2,3-(i]pyrimidin-4- yl)benzo [b] thiophene- 5 -carbonitrile ;

l-(2-(2-(4-(2-(Pyrrolidin-l-yl)ethoxy)phenylamino)-7H-pyrrolo[2,3-(i]pyrimidin-4- yl)benzo[b]thiophen-5-yl)pentan-l-one; 5-(2-(3-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-^]pyrimidin-4-yl)-3- methylthiophene-2-carbonitrile;

4-(4-Methylthiophen-2-yl)-N-(4-moφholin-4-ylphenyl)-7H-pyrrolo[2,3-<i]pyrimidin-2-amine;

N-(4-(2-(Dimethylamino)ethoxy)phenyl)-4-(4-methylthiophen-2-yl)-7H-pyrrolo[2,3- d] pyrimidin-2- amine;

4-(4-Methylthiophen-2-yl)-N-[4-(l,3-oxazol-5-yl)phenyl]-7H-pyrrolo[2,3-^]pyrimidin-2- amine;

N-{4-[2-(lH-Benzimidazol-2-yl)ethyl]phenyl}-4-(4-methylthiophen-2-yl)-7H-pyrrolo[2,3- d] pyrimidin-2- amine ;

4-(4-Methylthiophen-2-yl)-N-[4-(2-moφholin-4-ylethoxy)phenyl]-7H-pyrrolo[2,3- d] pyrimidin-2- amine ;

N-{4-[2-(4-Methylpiperazin-l-yl)ethoxy]phenyl}-4-(4-methylthiophen-2-yl)-7H-pyrrolo[2,3- d] pyrimidin-2- amine ;

N-{4-[(l-Methylpiperidin-4-yl)oxy]phenyl}-4-(4-methylthiophen-2-yl)-7H-pyrrolo[2,3- d] pyrimidin-2- amine ;

[4-(4-Methyl-thiophen-2-yl)-7H-pyrrolo[2,3-J]pyrimidin-2-yl]-[3-(2-pyrrolidin-l-yl-ethoxy)- phenyl] -amine;

[4-(4-Methyl-thiophen-2-yl)-7Η-pyrrolo[2,3-d]pyrimidin-2-yl]-[4-(2-pyrrolidin-l-yl-ethoxy)- phenyl] -amine;

[4-(5-Methyl-thiophen-2-yl)-7H-pyrrolo[2,3-J]pyrimidin-2-yl]-[4-(2-pyrrolidin-l-yl-ethoxy)- phenyl] -amine;

3-(2-(2-(4-((2-methyl-lΗ-imidazol-l-yl)methyl)phenylamino)-7Η-pyrrolo[2,3-d]pyrimidin-4- yl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-3-oxopropanenitrile;

(E)-3-methyl-5-(2-(4-(2-(pyrrolidin-l-yl)ethoxy)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)thiophene-2-carbaldehyde oxime; 4-(4-methyl-5-(lH-tetrazol-5-yl)thiophen-2-yl)-N-(4-(2-(pyrrolidin-l-yl)ethoxy)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine;

N-(4-(azepan-l-ylmethyl)phenyl)-4-(4-methylthiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2- amine;

N-(3-(4-methylpiperazin-l-yl)phenyl)-4-(5-(moφholinosulfonyl)-4,5,6,7-tetrahydrothieno[3,2- c]pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine;

(3,5-dimethylisoxazol-4-yl)(2-(2-(3-(4-methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methanone;

(2,5-dimethyloxazol-4-yl)(2-(2-(3-(4-methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methanone;

(5-methylisoxazol-3-yl)(2-(2-(3-(4-methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methanone;

(l-methyl-lH-pyrazol-4-yl)(2-(2-(3-(4-methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methanone; and

(l,3-dimethyl-lH-pyrazol-4-yl)(2-(2-(3-(4-methylpiperazin-l-yl)phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methanone;

or pharmaceutically acceptable salts, prodrugs, N-oxides, and hydrates thereof.

[0073] Contemplated herein also compositions that include the disclosed compounds and a pharmaceutically acceptable carrier.

Dosages

[0074] The dosage of any compositions of the present invention will vary depending on the symptoms, age and body weight of the patient, the nature and severity of the disorder to be treated or prevented, the route of administration, and the form of the subject composition. Any of the subject formulations may be administered in a single dose or in divided doses. Dosages for the compositions of the present invention may be readily determined by techniques known to those of skill in the art or as taught herein.

[0075] In certain embodiments, the dosage of the subject compounds will generally be in the range of about 0.01 ng to about 10 g per kg body weight, specifically in the range of about 1 ng to about 0.1 g per kg, and more specifically in the range of about 100 ng to about 10 mg per kg.

[0076] An effective dose or amount, and any possible affects on the timing of administration of the formulation, may need to be identified for any particular composition of the present invention. This may be accomplished by routine experiment as described herein, using one or more groups of animals (preferably at least 5 animals per group), or in human trials if appropriate. The effectiveness of any subject composition and method of treatment or prevention may be assessed by administering the composition and assessing the effect of the administration by measuring one or more applicable indices, and comparing the post-treatment values of these indices to the values of the same indices prior to treatment.

[0077] The precise time of administration and amount of any particular subject composition that will yield the most effective treatment in a given patient will depend upon the activity, pharmacokinetics, and bioavailability of a subject composition, physiological condition of the patient (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage and type of medication), route of administration, and the like. The guidelines presented herein may be used to optimize the treatment, e.g., determining the optimum time and/or amount of administration, which will require no more than routine experimentation consisting of: monitoring the subject and adjusting the dosage and/or timing.

[0078] While the subject is being treated, the health of the patient may be monitored by measuring one or more of the relevant indices at predetermined times during the treatment period. Treatment, including composition, amounts, times of administration and formulation, may be optimized according to the results of such monitoring. The patient may be periodically reevaluated to determine the extent of improvement by measuring the same parameters. Adjustments to the amount(s) of subject composition administered and possibly to the time of administration may be made based on these reevaluations. [0079] Treatment may be initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum therapeutic effect is attained.

[0080] The use of the subject compositions may reduce the required dosage for any individual agent contained in the compositions because the onset and duration of effect of the different agents may be complimentary.

[0081] Toxicity and therapeutic efficacy of subject compositions may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 and the ED50.

[0082] The data obtained from the cell culture assays and animal studies may be used in formulating a range of dosage for use in humans. The dosage of any subject composition lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For compositions of the present invention, the therapeutically effective dose may be estimated initially from cell culture assays.

Formulations

[0083] The compositions of the present invention may be administered by various means, depending on their intended use, as is well known in the art. For example, if compositions of the present invention are to be administered orally, they may be formulated as tablets, capsules, granules, powders or syrups. Alternatively, formulations of the present invention may be administered parenterally as injections (intravenous, intramuscular or subcutaneous), drop infusion preparations, suppositories or administration intranasally (for example, to deliver a dosage to the brain via the nose or to deliver a dosage to the nose directly) or by inhalation (e.g. to treat a condition of the respiratory tract or to pretreat or vaccinate via the respiratory tract). For application by the ophthalmic mucous membrane route, compositions of the present invention may be formulated as eyedrops or eye ointments. These formulations may be prepared by conventional means, and, if desired, the compositions may be mixed with any conventional additive, such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent. [0084] In formulations of the subject invention, wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may be present in the formulated agents.

[0085] Subject compositions may be suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of composition that may be combined with a carrier material to produce a single dose vary depending upon the subject being treated, and the particular mode of administration.

[0086] Methods of preparing these formulations include the step of bringing into association compositions of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association agents with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0087] Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), each containing a predetermined amount of a subject composition thereof as an active ingredient. Compositions of the present invention may also be administered as a bolus, electuary, or paste.

[0088] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0089] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.

[0090] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[0091] Suspensions, in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. [0092] Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non- irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.

Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0093] Dosage forms for transdermal administration of a subject composition includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0094] The ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0095] Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0096] Compositions and compounds of the present invention may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions.

[0097] Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.

[0098] Dosages for administration by nasal delivery, e.g. delivered to or via the nasal cavity, can be applied as drops, ointments, gels, mists/sprays (aqueous or nonaqueous), aerosols (liquids, suspensions or dry powders), powders, or combinations thereof. Such delivery can be achieved by commercially available devices such as droppers, nasal sprayers, metered dose aerosols, or other mechanisms known in the art. Pharmaceutical formulations for inhalation and/or delivery to the nose, may contain from 1% to 20% by weight of a penetrator enhancer (for example, surfactants, e.g. sugar esters, sugar ethers, carbohydrate esters) which may allow enhanced nose permeability of the active agent.

[0099] Dosages for administration by inhalation or by delivered to or via the lung, can be applied as mists/sprays (aqueous or nonaqueous), aerosols (liquids, suspensions or dry powders), liquids or suspensions (aqueous or nonaqueous), powders, or combinations thereof. Such delivery can be achieved by commercially available devices such as 1) nebulizers, 2) metered dose inhalers, 3) dry powder inhalers, 4) soft mist inhalers, or by instillation or insufflation, or other mechanisms and/or devices known in the art.

[0100] For topical ocular administration compositions of this invention may take the form of solutions, gels, ointments, suspensions or solid inserts, formulated so that a unit dosage comprises a therapeutically effective amount of the active component or some multiple thereof in the case of a combination therapy.

[0101] Pharmaceutical compositions of this invention suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically- acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. [0102] Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

Methods

[0103] Treatment or amelioration of disease states and pathological conditions that implicate JAK, e.g. JAK2, pathways are contemplated herein, and such treatment comprises administering one or more of the disclosed compounds, such as those recited in Formulas I, II, or III, or a composition as described herein comprising a disclosed compound. In some embodiments, the disclosed compounds may inhibit or modulate one or more of the JAK family, e.g, JAKl, JAK2, JAK3, and/or TYK2, and/or may inhibit or modulate KDR. In other embodiments, the disclosed compounds may for example inhibit JAK2 but may not substantially modulate JAK3 and/or KDR.

[0104] Methods of treating a patient in need thereof, e.g. suffering from a disease where inihibition of kinases are useful, for example, immunological and autoimmune disorders, inflammatory disease, diabetes, fibrosis of the liver and/or kidney, atherosclerosis, and ocular diseases are contemplated.

[0105] Because JAKs appear to play a crucial role in regulating cell behavior induced by a number of cytokines, treatment of indications driven by a dysregulation of signaling pathways normally associated with cytokine regulation may include compounds which modulate the activity of the JAKs, such as those recited in Formulas I, II or III is contemplated, such as the treatment of immune and inflammatory diseases, e.g. rheumatoid arthritis (RA), psoriatic arthritis, asthma, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, type I diabetes mellitus, myasthenia gravis, thyroiditis, myocarditis, psoriasis, immunoglobulin nephropathies, uveitis, iritis, scleritis, conjunctivitis, graft versus host disease and dermatitis. Particularly, methods of treating asthma and/or chronic obstructive pulmonary disease (COPD) are contemplated. [0106] Somatic mutations in the hematopoietic system leading to activation of the JAK pathway has been linked to the myeloproliferative disorders polycythemia vera, essential thrombocythemia and myeloid metaplasia with myelofibrosis. Similarly, upregulation of the JAK pathway may contribute to the myeloproliferative disorders chronic myelogenous leukemia, chronic myelomomocytic leukemia, thallasemia gravis, hypereosinophilic syndrome, and systemic mast cell disease. Specifically contemplated herein are methods for treating cancers, e.g. cancers are associated with activation of Janus kinases including acute myeloid leukemia, hepatocellular carcinoma, multiple myeloma, Hodgkin's lymphomas and T cell leukemia/lymphoma, wherein the method includes administrating a disclosed compound.

[0107] The angiogenic role of JAK2 downstream of the EPO receptor has been implicated in ocular diseases such as Age Related Macular Degeneration (AMD), diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR), and treatement of one or more of these diseases is contemplated. In an embodiment, a method of treating an ocular or other disease is contemplated that includes administration of a disclosed compound that modulates JAK and in some embodiments, inhibits VEGFr.

[0108] Also contemplated herein is a method for treating or ameliorating transplant rejection that includes administering an instantly disclosed compound.

[0109] In an embodiment, a method for treating or ameliorating rheumatoid arthritis that includes administering an instantly disclosed compound is contemplated.

[0110] Dysregulation in the hematopoietic stem cells of the myeloid compartment may lead to related myeloproliferative disorders (MPDs) including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), and to acute myeloid leukemia (AML) Underlying each of these myeloid diseases may be a cytokine-independent activation of molecular signaling pathways critical for the proliferation and aberrant survival of the cells associated with the disease's pathology. For example, a majority of PV, ET, and MF patients harbor an activating valine to phenylalanine point mutation at residue 617 in Janus kinase 2 (JAK2^V617F) that may be necessary and sufficient for myeloid expansion and the symptoms manifested by these diseases. Along with JAK2^V617F, there are less prevalent tyrosine kinase mutations, all of which constitutively activate JAK2 in these 3 diseases such as JAK2^T875N, exon 12 mutations in JAK2, and mutations in the upstream thrombopoietin receptor (MPL^W515I7K). Without being bound by any theory, JAK2 activation leads to phosphorylation of signal transducer and activator of transcription (STAT) proteins, transcription factors that stimulate the cell's genetic machinery to induce proliferation and prevent apoptosis. Similarly, AML features ligand-independent activation of the JAK-STAT pathway in the majority of patients. Although there is no predominant known mutation that leads to activation of the JAK-STAT pathway in AML, approximately 30% of AML patients appear to have this activation mediated through mutations in the FMS-like receptor tyrosine kinase 3 (FLT3). Methods of treating a patient suffering from acute leukaemias, myeloid and lymphoid malignancies or myeloproliferative disorders such as polycythemia vera, myelofibrosis and essential thrombocythemia are contemplated and may comprise administering an effective amount of a disclosed compound, such as those recited in Formulas I, II, or III or a composition comprising a disclosed compound. In an embodiment, a method of treatment of AML, PV, ET and MT, for example, in patients with mutations in FLT3, is contemplated, comprising administering a disclosed compound, e.g. a compound of Formulas I, II, or III.

[0111] Treatment of other cancers is contemplated comprising administering an effective amount of a disclosed compound. The treatment of cancers can include, but are not limited to, an alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer, breast cancer, ovarian cancer, prostate cancer, leukemia (including acute myelogenous leukemia and chronic myelogenous leukemia), kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer or brain cancer.

[0112] Also contemplated herein are methods of treating ocular neovasculariaztion, infantile haemangiomas, organ hypoxia, vascular hyperplasia, organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type 1 diabetes and complications from diabetes, inflammatory disease, acute pancreatitis, chronic pancreatitis, asthma, allergies, adult respiratory distress syndrome, cardiovascular disease, liver disease, other blood disorders, asthma, rhinitis, atopic, dermatitits, autoimmune tliryroid disorders, ulerative colitis, Crohn's disease, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, conditions associated with cytokines, and other autoimmune diseases including glomerulonephritis,, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopy (e.g., allergic asthma, atopic dermatitis, or allergic rhinitis), chronic active hepatitis, myasthenia graivs, inflammatory bowel disease, graft vs host disease, neurodegenerative diseases including motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral scelerosis, Huntington's disease, cerebral ischemia, or neurodegenerative disease caused by traumatic injury, stroke, gluatamate neurtoxicity or hypoxia; ischemic/reperfusion injury in stroke, myocardial ischemica, renal ischemia, heart attacks, cardiac hypertrophy, atherosclerosis and arteriosclerosis, and platelet aggregation. Such treatment includes administering an effective amount of a disclosed compound.

[0113] Examples of some additional diseases and disorders that can be treated using a disclosed include cell mediated hypersensitivity (allergic contact dermatitis, hypersensitivity pneumonitis), rheumatic diseases (e.g., systemic lupus erythematosus (SLE), juvenile arthritis, Sjogren's Syndrome, scleroderma, polymyositis, ankylosing spondylitis, psoriatic arthritis), viral diseases (Epstein Barr Vims, Hepatitis B, Hepatitis C, HIV, HTLVl, Vaiceila- Zoster Virus, Human Papilloma Virus), food allergy, cutaneous inflammation, and immune suppression induced by solid tumors.

[0114] One embodiment provides for a process for forming a compound of Formula I comprising reacting a compound of Formula IV:

IV

wherein Y is a boronic acid or halogen, with R₂-NH₂ to obtain the compound of Formula I. In

a further embodiment , R₂ is

[0115] Another embodiment provides a process for forming a compound of formula II comprising reacting a compound of formula V:

V

wherein Y is a boronic acid or halogen, with a compound of Formula VI:

VI

to obtain the compound of Formula II. In some embodiments, the compound of Formula II is a compound of Formula Ilia or IHb.

[0116] The examples which follow are intended in no way to limit the scope of this invention but are provided to illustrate how to prepare and use compounds of the present invention. Many other embodiments of this invention will be apparent to one skilled in the art.

EXAMPLES

General Methods

[0117] All experiments were performed under anhydrous conditions (i.e. dry solvents) in an atmosphere of argon, except where stated, using oven-dried apparatus and employing standard techniques in handling air- sensitive materials. Aqueous solutions of sodium bicarbonate

(NaHCO₃) and sodium chloride (brine) were saturated. Analytical thin layer chromatography (TLC) was carried out on Merck Kieselgel 60 F₂₅₄ plates with visualization by ultraviolet and/or anisaldehyde, potassium permanganate or phosphomolybdic acid dips. Reverse-phase HPLC chromatography was carried out on Gilson 215 liquid handler equipped with Waters SymmetryShield™ RP18 7μm (40 x 100mm) Prep-Pak cartridge. Mobile phase consisted of standard acetonitrile (ACN) and DI Water, each with 0.1% TFA added. Purification was carried out at a flow rate of 4OmL/ min. NMR spectra: ¹H Nuclear magnetic resonance spectra were recorded at 500 MHz. Data are presented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, dd = doublet of doublets, m = multiplet, br s = broad singlet), coupling constant (J/Hz) and integration. Coupling constants were taken directly from the spectra and are uncorrected. Low resolution mass spectra: Electrospray (ES+) ionization was used. The protonated parent ion (M+H) or fragment of highest mass is quoted. Analytical gradient consisted of 10% ACN in water ramping up to 100% ACN over 5 min unless otherwise stated.

Example 1: Preparation of 2-Chloro-4-(4-methyl-thiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (1)

[0118] To a round bottomed flask was charged with 2,4-dichloro-7H-pyrrolo[2,3- d]pyrimidine (0.20 g, 1.1 mmol), 4-methylthiophene-2-boronic acid (0.20 g, 1.4 mmol) and Pd(PPh₃ )₄ (0.10 g, 0.087 mmol). DMF (6 mL) was added to the above mixture followed by aqueous sodium carbonate (2 M; 1.5 mL, 3.0 mmol). The suspension was heated at 140 ⁰C for 2 h and then allowed to cool to room temperature. The mixture was filtered, the filtered solid washed with DCM and the filtrate concentrated. The residue was purified by flash column chromatography on silica gel (hexanes to 60% EtOAc/hexanes) to afford the title compound as a yellow solid (80 mg, 30%). MS (ES+): m/z 250 (M+Η)⁺

Example 2: Preparation of [4-(4-Methyl-piperazin-l-yl)-phenyl]-[4-(4-methyl-thiophen-2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-2-yl]-amine

[0119] A suspension of 1 (80 mg, 0.32 mmol), 4-(4-methyl-piperazin-l-yl)-phenylamine (90 mg, 0.47 mmol), Pd₂(dba)₃ (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 ⁰C for 20 min. After cooling to room temperature, the resulting mixture was filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO₃ solution (25 mL). The combined aqueous layers were extracted with EtOAc (2 x 25 mL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a light brown solid (8 mg, 6%).

[0120] ¹H NMR (500 MHz, DMSO-d₆): δ 2.24 (s, 3H), 2.32 (s, 3H), 2.45-2.55 (m, 4H), 3.06 (t, J = 4.6 Hz, 4H), 6.81 (dd, J = 3.6, 1.7 Hz, IH), 6.88 (d, J = 9.0 Hz, 2H), 7.23 (dd, J = 3.6, 2.2 Hz, IH), 7.37 (t, J= 1.1 Hz, IH), 7.72 (d, J= 9.1 Hz, 2H), 7.89 (s, IH), 8.91 (s, IH), 11.5 (s, IH). MS (ES+): m/z 405 (M+H)⁺

Example 3: Preparation of 4-(4-Methyl-thiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (2)

[0121] To a microwave reaction tube was charged with 4-chloro-7H-pyrrolo[2,3- d]pyrimidin-2-ylamine (0.14 g, 0.85 mmol), 4-methylthiophene-2-boronic acid (0.15 g, 1.1 mmol) and Pd(PPlIs)₄ (0.10 g, 0.087 mmol). DMF (5 niL) was added to the above mixture followed by aqueous sodium carbonate (2 M; 1.0 mL, 2.0 mmol). The reaction tube was sealed and the suspension irradiated with microwave at 160 ⁰C for 20 min. After cooling to room temperature, the mixture was filtered, the filtered solid washed with DCM and the filtrate concentrated. The crude product was purified by column chromatography on silica gel (hexanes to 50% EtOAc/hexanes) to afford the title compound (0.18 g, 92%) as a yellow solid. MS (ES+): m/z 231 (M+H)⁺

[0122] Example 4: Preparation of 4-[4-(4-Methyl-thiophen-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino] -/V-(2-pyrrolidin- 1 -yl-ethyl)-benzenesulfonamide

[0123] A suspension of 2 (0.18 g, 0.78 mmol), 4-bromo-N-(2-pyrrolidin-l-yl-ethyl)- benzenesulfonamide (0.35 g, 1.1 mmol), Pd₂(dba)₃ (50 mg, 0.055 mmol), Xantphos (65 mg, 0.11 mmol) and cesium carbonate (0.50 g, 1.5 mmol) in dioxane/DMF (1/1, 6 mL) was sealed in a microwave reaction tube and irradiated with microwave at 170 ⁰C for 20 min. After cooling to room temperature, the resulting mixture was filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by ΗPLC. The fractions were combined and poured into saturated NaHCO₃ solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a yellow solid (10 mg, 3%).

[0124] ¹H NMR (500 MHz, DMSO-d₆): δ 1.60-1.73 (m, 4H), 2.34 (s, 3H), 2.40-2.60 (m, 4H), 2.80-2.90 (m, 2H), 3.20-3.30 (m, 2H, underneath solvent peak), 6.92 (dd, J = 3.5, 1.5 Hz, IH), 7.34 (br s, IH), 7.38 (dd, J = 5.7, 2.3 Hz, IH), 7.42 (s, IH), 7.69 (d, J = 8.9 Hz, 2H), 7.96 (s, IH), 8.09 (d, J = 8.9 Hz, 2H), 9.76 (s, IH), 11.8 (s, IH) MS (ES+): m/z 483 (M+H)⁺ Example 5: Preparation of 2-Chloro-4-(5-methyl-thiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidine

(3)

3

[0125] To a round bottomed flask was charged with 2,4-dichloro-7H-pyrrolo[2,3- d]pyrimidine (0.40 g, 2.1 mmol), 5-methylthiophene-2-boronic acid (0.50 g, 3.5 mmol) and Pd(PPh₃ )₄ (0.20 g, 0.17 mmol). DMF (10 mL) was added to the above mixture followed by aqueous sodium carbonate (2 M; 3.0 mL, 6.0 mmol). The suspension was heated at 120 ⁰C for 1 h and then allowed to cool to room temperature. The mixture was filtered, the filtered solid washed with DCM and the filtrate concentrated. The residue was triturated in MeOH and the solid filtered to afford the title compound as a brown solid (0.30 g, 56%). The material was used in the next step without purification. MS (ES+): m/z 250 (M+Η)⁺

Example 6: Preparation of [4-(4-Methyl-piperazin-l-yl)-phenyl]-[4-(5-methyl-thiophen-2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-2-yl]-amine

[0126] A suspension of 3 (0.10 g, 0.40 mmol), 4-(4-methyl-piperazin-l-yl)-phenylamine (0.10 g, 0.52 mmol), Pd₂(dba)₃ (25 mg, 0.027 mmol), Tri tert-butylphosphine (IM in toluene, 0.1 mL) and potassium te/t-butoxide (0.20 g, 1.8 mmol) in dioxane/DMF (1/1, 6 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 ⁰C for 30 min. After cooling to room temperature, the resulting mixture was filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by ΗPLC. The fractions were combined and poured into saturated NaHCO₃ solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 rnL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a beige solid (15 mg, 9%).

[0127] ¹H NMR (500 MHz, DMSO-d₆): δ 2.28 (s, 3H), 2.45-2.55 (m, 4H), 2.54 (s, 3H), 3.00-3.10 (m, 4H), 6.77 (dd, J = 3.5, 1.8 Hz, IH), 6.88 (d, J = 9.1 Hz, 2H), 6.97 (d, J= 3.7 Hz, IH), 7.20 (dd, J = 5.7, 2.5 Hz, IH), 7.71 (d, J= 8.9 Hz, 2H), 7.86 (d, J= 3.6 Hz, IH), 8.88 (s, IH), 11.5 (s, IH) MS (ES+): m/z 405 (M+H)⁺

Example 7: Preparation of fert-Butyl[(lZ)-[(fert-butoxycarbonyl)amino]{ [4-(2-pyrrolidin-l- ylethoxy ) phenyl] amino jmethylidene] carbamate (4)

4

[0128] A mixture of (fer^-butoxycarbonylimino-pyrazol-l-yl-methy^-carbamic acid tert- butyl ester (5.0 g, 16.1 mmol) and 4-(2-pyrrolidin-l-yl-ethoxy)-phenylamine (4.0 g, 19.4 mmol) in DMF (10 mL) was stirred at room temperature for 17 h. The reaction mixture was concentrated and the residue taken in water (50 mL). The resulting solid was filtered, washed with water and dried under high vacuum to afford the title compound as an off white solid (7 g, 97%). The material was used in the next step without purification. MS (ES+): m/z 449 (M+H)⁺, 249 (M+l-2 Boc)⁺

Example 8: Preparation of N-[4-(2-Pyrrolidin-l-yl-ethoxy)-phenyl]-guanidine TFA salt (5)

[0129] A solution of 4 (2.0 g, 4.5 mmol) in 50% TFA/DCM (10 niL) was stirred at room temperature for 17 h. The solution was concentrated to afford the title compound (quant, yield), which was used in the next step without purification. MS (ES+): m/z 249 (M+H)⁺

Example 9: Preparation of 2-[4-(2-Pyrrolidin-l-yl-ethoxy)-phenylamino]-7H-pyrrolo[2,3- d]pyrimidin-4-ol (6)

[0130] To a microwave reaction tube was charged with 5 (1.6 g, 4.5 mmol), 2-cyano-4,4- diethoxy-butyric acid ethyl ester (0.15 g, 7.4 mmol) and NaOMe (25% by wt in MeOH; 10 mL) in EtOH (5 mL). The reaction tube was sealed and the solution irradiated with microwave at 160 ⁰C for 30 min. After cooling to room temperature, the mixture was concentrated. The residue was taken up in water (10 mL) and the pΗ adjusted to 1 with 6M of HCl. The resulting solution was stirred at room temperature for 25 min and then the pΗ adjusted to 9 with concentrated NH₄OH. The resulting solid was filtered, washed with water and dried under high vacuum to afford the title compound as a brown solid (0.8 g, 52%). The material was used in the next step without purification. MS (ES+): m/z 340 (M+H)⁺

Example 10: Preparation of (4-Chloro-7H-pyrrolo[2,3-<i]pyrimidin-2-yl)-[4-(2-pyrrolidin-l-yl- ethoxy) -phenyl] -amine (7)

[0131] A solution of 6 ( 1.4 g, 4.1 mmol) in POCl₃ (5 niL) was heated at 120 ⁰C for 20 min. After cooling to room temperature, the resulting dark solution was poured into ice water slowly and the pH adjusted to 9-10. The resulting solid was filtered, washed with water and dried under high vacuum to afford the title compound as a brown solid (1.4 g, 95%). The material was used in the next step without purification. MS (ES+): m/z 358 (M+H)⁺

Example 11: Preparation of [4-(5-Chloro-thiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-[4- (2-pyrrolidin- 1 -yl-ethoxy)-phenyl] -amine

[0132] To a microwave reaction tube was charged with 7 (90 mg, 0.25 mmol), 5- chlorothiophene-2-boronic acid (60 mg, 0.37 mmol) and Pd(PPh₃)₄ (30 mg, 0.026 mmol). DMF (3 mL) was added to the above mixture followed by 2 M of sodium carbonate (0.5 mL). The reaction tube was sealed and the suspension irradiated with microwave at 140 ⁰C for 20 min. After cooling to room temperature, the mixture was filtered, the filtered solid washed with DCM and the filtrate concentrated. The crude product was purified by ΗPLC, the fractions combined and poured into saturated NaHCO₃ solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a light brown solid (35 mg, 32%).

[0133] ¹H NMR (500 MHz, DMSO-d₆): δ 1.68-1.78 (m, 4H), 2.55-2.70 (m, 4H), 2.80- 2.90 (m, 2H), 4.08 (t, J = 5.0 Hz, 2H), 6.83 (dd, J = 3.7, 1.7 Hz, IH), 6.90 (d, J= 9.1 Hz, 2H), 7.28 (d, J = 4.0 Hz, 2H), 7.72 (d, J = 9.1 Hz, 2H), 7.94 (d, J= 4.0 Hz, IH), 9.05 (s, IH), 11.6

(s, IH)

MS (ES+): m/z 440 (M+H)⁺

Example 12: Preparation of (5-{2-[4-(2-Pyrrolidin-l-yl-ethoxy)-phenylamino]-7H-pyrrolo[2,3- d]pyrimidin-4-yl } -thiophen-2-yl)-methanol

[0134] To a microwave reaction tube was charged with 7 (85 mg, 0.24 mmol), 5- hydroxymethyl-2-boronic acid (50 mg, 0.32 mmol) and Pd(PPh₃)₄ (30 mg, 0.026 mmol).

DMF (3 mL) was added to the above mixture followed by 2 M of sodium carbonate (0.5 mL). The reaction tube was sealed and the suspension irradiated with microwave at 140 ⁰C for 20 min. After cooling to room temperature, the mixture was filtered, the filtered solid washed with DCM and the filtrate concentrated. The crude product was purified by ΗPLC, the fractions combined and poured into saturated NaHCO₃ solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a yellow solid (50 mg, 48%).

[0135] ¹H NMR (500 MHz, DMSO-d₆): δ 1.68-1.72 (m, 4H), 2.50-2.60 (m, 4H), 2.78- 2.84 (m, 2H), 4.04 (t, J = 4.9 Hz, 2H), 4.71 (d, J= 5.9 Hz, 2H), 5.61 (t, J= 5.8 Hz, IH), 6.79 (dd, J = 3.6, 1.8 Hz, IH), 6.88 (d, J= 9.1 Hz, 2H), 7.09 (d, J= 3.7 Hz, IH), 7.23 (dd, J= 3.5, 2.4 Hz, IH), 7.76 (d, J = 9.1 Hz, 2H), 7.91 (d, J = 3.8 Hz, IH), 8.98 (s, IH), 11.5 (s, IH) MS (ES+): m/z 436 (M+H)⁺ Example 13: Preparation of 2,4-Dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (8)

8

[0136] In a flask 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 5.3 mmol) in DMF (30 rnL) was added NaH (60% in mineral oil, 0.21 g, 5.3 mmol). After stirring 5 min at room temperature the reaction mixture was added tosyl chloride (1.0 g, 5.3 mmol) and stirred 1 h at room temperature. The reaction mixture was diluted with H₂O (100 mL) and filtered. The filtered solid was washed with H₂O (20 mL) and dried 5 h under house vacuum at 80 ⁰C to afford the title compound as a yellow solid (1.6 g, 90%). 1H NMR (500 MHz, DMSO-d₆): δ 2.38 (s, 3H), 6.98 (d, J = 4.1 Hz, IH), 7.50 (d, J = 8.3 Hz, 2H), 8.03 (d, J = 8.5 Hz, 2H), 8.11 (d, J = 4.1 Hz, IH) MS (ES+): m/z 343 (M+H)⁺

Example 14: Preparation of 2-Chloro-4-(4-methylthiophen-2-yl)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidine (9)

[0137] To a solution of 8 (0.80 g, 4.26 mmol), 4-methylthiophene-2-boronic acid (0.60 g, 4.26 mmol) and Pd(PPh₃)₄ (0.49 g, 0.43 mmol) in DMF was added Na₂CO₃ (2.0 M, 3.6 mL). The reaction mixture was heated 1 h at 120 ⁰C and then cooled to room temperature. The resulting mixture was filtered through a pad of silica gel. The filtrate was concentrated and purified by silica gel chromatography (hexanes/EtOAc 100:0 to 70:30 gradient) to afford the title compound as a yellow solid (0.58 g, 55%). [0138] ¹H NMR (500 MHz, DMSO-d₆): δ 2.29 (s, 3H), 2.37 (s, 3H), 7.42 (d, J = 4.1 Hz, IH), 7.49 (d, J = 8.3 Hz, 2H), 7.55 (s, IH), 8.03 (d, J= 8.4 Hz, 2H), 8.07 (s, IH), 8.09 (d, J -- 4.1 Hz, 2H) MS (ES+): m/z 404 (M+H)⁺

Example 15: Preparation of 4-(4-Methylthiophen-2-yl)-/V-(4-(pyridin-4-ylmethyl)phenyl)-7H- pyrrolo[2,3-J]pyrimidin-2-amine

[0139] In a microwave vial was sequentially added 9 (0.150 g, 0.37 mmol), Pd(OAc)₂ (0.008 g, 0.037 mmol), DMF (3 mL), 4-(4-pyridylmethyl)aniline (0.082 g, 0.45 mmol), P(f- Bu)₃ (1 M in toluene, 0.074 mL, 0.074 mmol), and triethylamine (0.52 mL, 3.71 mmol). The reaction mixture was heated 20 min at 180 ⁰C in a Biotage microwave reactor. The resulting mixture was separated by preparative ΗPLC. Fractions that contained the desired product were combined, neutralized with saturated Na₂CO₃, and extracted with EtOAc. The organic layer was dried over MgSO₄ and concentrated to afford the tosylated intermediate as brown oil. The brown oil was re-dissolved in TΗF (2 mL) and tetrabutylammonium fluoride (0.15 mL, 1.0 M in TΗF, 0.15 mmol) was added. The reaction mixture was stirred 15 min at 70 ⁰C and then cooled to room temperature. The resulting mixture was concentrated and purified by silica gel chromatography (hexanes/EtOAc 100:0 to 0:100 gradient) to afford the title compound as a yellow solid (0.013 g, 9%).

[0140] ¹H NMR (500 MHz, DMSO-d₆): δ 2.32 (s, 3H), 3.90 (s, 2H), 6.84 (dd, J = 3.6, 1.4 Hz, IH), 7.15 (d, J = 8.6 Hz, 2H), 2.55 (d, J = 6.1 Hz, 2H), 2.79 (dd, J = 3.7, 2.8 Hz, IH), 7.37 (s, IH), 7.83 (d, J = 8.7 Hz, 2H), 7.90 (s, IH), 8.45 (d, J = 6.1 Hz, 2H), 9.16 (s, IH), 11.58 (s, IH)

Example 16: Preparation of N-(4-((lH-l,2,4-Triazol-l-yl)methyl)phenyl)-4-(4- methylthiophen-2-yl)-7H-pyrrolo[2,3-<i]pyrimidin-2-amine

[0141] In a microwave vial was sequentially added 9 (0.150 g, 0.37 mmol), Pd(OAc)₂ (0.008 g, 0.037 mmol), DMF (3 mL), 4-(lH-l,2-4-triazol-l-ylmethyl)aniline (0.077 g, 0.45 mmol), P(Z-Bu)₃ (1 M in toluene, 0.074 mL, 0.074 mmol), and triethylamine (0.52 mL, 3.71 mmol). The reaction mixture was heated 20 min at 180 ⁰C in a Biotage microwave reactor and then cooled to room temperature. The resulting mixture was added a solution of 1.0 M tetrabutylammonium fluoride in TΗF (0.5 mL) and stirred 20 min at 110 ⁰C. Upon cooling to room temperature the resulting mixture was separated by preparative ΗPLC. Fractions that contained the desired product were combined, neutralized with saturated Na₂CO₃, and extracted with EtOAc. The organic layer was dried over MgSO₄ and concentrated to afford the title compound as a yellow solid (0.080 g, 56%).

[0142] ¹H NMR (500 MHz, DMSO-d₆): δ 2.32 (s, 3H), 5.33 (s, 2H), 6.85 (d, J = 3.6 Hz, IH), 7.23 (d, J = 8.6 Hz, 2H), 7.29 (d, J = 3.6 Hz, IH), 7.38 (s, IH), 7.87 (d, J = 8.7 Hz, 2H), 7.91 (s, IH), 7.96 (s, IH), 8.63 (s, IH), 9.27 (s, IH), 11.66 (s, IH) MS (ES+): m/z 388 (M+H)⁺

Example 17: Preparation of 4-(4-Methylthiophen-2-yl)-/V-(4-(pyridin-3-yl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine

[0143] In a microwave vial was sequentially added 9 (0.150 g, 0.37 mmol), Pd(OAc)₂ (0.008 g, 0.037 mmol), DMF (3 mL), 4-(pyridine-3-yl)aniline (0.076 g, 0.45 mmol), P(J-Bu)₃ (1 M in toluene, 0.074 mL, 0.074 mmol), and triethylamine (0.52 mL, 3.71 mmol). The reaction mixture was heated 20 min at 180 ⁰C in a Biotage microwave reactor and then cooled to room temperature. The resulting mixture was added a solution of 1.0 M tetrabutylammonium fluoride in THF (0.5 mL) and stirred 20 min at 110 ⁰C. Upon cooling to room temperature the resulting mixture was separated by preparative HPLC. Fractions that contained the desired product were combined, neutralized with saturated Na₂CO₃, and extracted with EtOAc. The organic layer was dried over MgSO₄ and concentrated to afford the title compound as a yellow solid (0.011 g, 8%).

[0144] ¹H NMR (500 MHz, DMSO-d₆): δ 2.28 (s, 3H), 3.35-3.40 (m, IH), 6.91 (dd, J = 3.7, 1.8 Hz, IH), 3.66 (dd, J = 3.5, 2.2 Hz, IH), 7.43 (s, IH), 7.86 (d, J = 8.8 Hz, IH), 7.96 (s, IH), 8.02 (dd, J = 8.1, 5.5 Hz, IH), 8.13 (s, 2H), 8.76 (d, J= 5.5, IH), 8.82 (d, J = 8.2 Hz, IH), 9.22 (d, J = 1.8 Hz, IH), 9.62 (s, IH), 11.80 (s, IH) MS (ES+): m/z 384 (M+H)⁺

Example 18: Preparation of 4-(4-Methylthiophen-2-yl)-N-(4-(piperidin-4-yloxy)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine

[0145] In a microwave vial was sequentially added 9 (0.150 g, 0.37 mmol), Pd(OAc)₂

(0.008 g, 0.037 mmol), DMF (3 mL), te/t-butyl 4-(4-aminophenoxy)piperidine-l-carboxylate (0.13 g, 0.45 mmol), P(Z-Bu)₃ (1 M in toluene, 0.074 niL, 0.074 mmol), and triethylamine (0.52 niL, 3.71 mmol). The reaction mixture was heated 20 min at 180 ⁰C in a Biotage microwave reactor and then cooled to room temperature. The resulting mixture was added a solution of 1.0 M tetrabutylammonium fluoride in THF (0.5 mL) and stirred 20 min at 110 ⁰C. Upon cooling to room temperature the resulting mixture was separated by preparative HPLC. Fractions that contained the desired product were combined, neutralized with saturated Na₂CO₃, and extracted with EtOAc. The organic layer was dried over MgSO₄ and concentrated to a yellow solid. The yellow solid was re-dissolved in CH₂Cl₂ (3 mL) and trifluoroacetic acid (0.5 mL) was added to the solution. The reaction mixture was stirred overnight at room temperature. The resulting mixture was added saturated Na₂CO₃ (5 mL) and extracted with EtOAc (10 mL). The organic layer was dried over MgSO₄ to afford the title compound as a yellow solid (0.019 g, 13%).

[0146] ¹H NMR (500 MHz, DMSO-d₆): δ 2.32 (s, 3H), 1.73-1.77 (m, 2H), 2.03-2.08 (m, 2H), 2.97-3.02 (m, 2H), 3.18-3.32 (m, 2H), 4.49-4.52 (m, IH), 6.83 (dd, J = 3.6, 1.6 Hz, IH), 6.94 (d, J = 9.1 Hz, 2H), 7.26 (dd, J = 3.6, 2.2 Hz, IH), 7.37 (s, IH), 7.97 (d, J = 9.1 Hz, 2H), 7.90 (s, IH), 9.04 (s, IH), 11.55 (s, IH) MS (ES+): m/z 406 (M+H)⁺

Example 19: Preparation of 4-(4-Methylthiophen-2-yl)-N-(4-(piperidin-l-ylmethyl)phenyl)- 7H-pyrrolo[2,3-d]pyrimidin-2-amine

[0147] In a microwave vial was sequentially added 9 (0.150 g, 0.37 mmol), Pd(OAc)₂ (0.008 g, 0.037 mmol), DMF (3 mL), 4-(piperidin-l-ylmethyl)aniline (0.085 g, 0.45 mmol), P(Z-Bu)₃ (1 M in toluene, 0.074 mL, 0.074 mmol), and triethylamine (0.52 mL, 3.71 mmol). The reaction mixture was heated 20 min at 180 ⁰C in a Biotage microwave reactor and then cooled to room temperature. The resulting mixture was added a solution of 1.0 M tetrabutylammonium fluoride in TΗF (0.5 mL) and stirred 20 min at 110 ⁰C. Upon cooling to room temperature the resulting mixture was separated by preparative HPLC. Fractions that contained the desired product were combined, neutralized with saturated Na₂CO₃, and extracted with EtOAc. The organic layer was dried over MgSO₄ and concentrated to afford the title compound as a yellow solid (0.016 g, 11%).

[0148] ¹H NMR (500 MHz, DMSO-d₆): δ 1.66-1.69 (m, 2H), 1.74-1.76 (m, 4H), 2.33 (s, 3H), 2.76-2.84 (m, 2H), 3.28 (d, J = 11.7 Hz, 2H), 4.16 (d, J = 5.1 Hz, 2H), 6.88 (dd, J = 3.6, 1.8 Hz, IH), 7.34 (dd, J = 3.5, 2.2 Hz, IH), 7.42 (s, IH), 7.48 (d, J = 8.6 Hz, 2H), 7.95 (s, IH), 7.98 (d, J = 8.7 Hz, 2H), 9.51 (s, IH), 10.24 (s, IH), 11.75 (s, IH) MS (ES+): m/z 404 (M+H)⁺

Example 20: Preparation of (5-(2-Chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)thiophen-2- yl)methanol (10)

10

[0149] To a solution of 2,4-dichloro-7H-pyrrolo[2,3-J]pyrimidine (188 mg, 1.0 mmol) in dimethoxyethane (DME, 10 mL) was added a solution of benzo[b]thiophen-2-yl-2-boronic acid (174 mg, 1.1 mmol) in EtOH (5 mL), 2.0 M Na₂CO₃ (2 mL), and tetrakis(triphenylphosphine)palladium (0) (Pd(PPh₃)₄, 115 mg, 0.1 mmol). The reaction mixture was heated at 110 ⁰C for 20 min under μ-wave. The hot solution was filtered and the solid was washed with EtOAc. The filtrate was washed with brine (50 mL). The aqueous was extracted with EtOAc (3 x 30 mL). Combined organic layer was dried (Na₂SO₄). The solvent was removed in vacuo. The residue was added MeOH and sonicated. The solid was collected by filtration. The title compound (165 mg, 62%) was afforded as a yellow solid.

Example 21: Preparation of (5-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)thiophen-2-yl)methanol

[0150] To a solution of 10 (80 mg, 0.3 mmol) in 1,4-dioxane (10 niL) and DMF (5 niL) was added 4-(4-methylpiperazin-l-yl)benzenamine (63 mg, 0.33 mmol), KO'Bu (134 mg, 1.2 mmol), Pd₂(dba)₃ (28 mg, 0.03 mmol), and 1.0 M tri-te/t-butylphosphine in toluene (0.09 mL, 0.09 mmol). The reaction mixture was heated at 150 ⁰C for 20 min under μ-wave. The solid was filtered off and the filtrate was washed with brine (1 x 50 mL). The organic solution was separated and dried (Na₂SO₄). The solvent was removed in vacuo. The crude product was purified by using HPLC. The HPLC fractions containing product were combined and neutralized with saturated NaHCO₃ (50 mL). The free base was extracted with EtOAc (2 x 10O mL). The organic layers were combined and dried (Na₂SO₄). The solvent was removed in vacuo. The residue was dissolved in MeOH (2 mL) and 4.0 M HCl solution (0.3 mL, 1.2 mmol) in dioxane was added. The solution was stirred for 5 min at room temperature and then solvent was removed in vacuo. The residue was dissolved in MeOH (1 mL) and anhydrous Et₂O (20 mL) was added. The solid was collected by centrifuging. The title compound (18 mg, 13%) was afforded as a yellow solid.

[0151] ¹H NMR (500 MHz, DMSO-d₆): δ 2.81 (d, J = 3.4 Hz, 3H), 3.06-3.10 (m, 2H), 3.15-3.19 (m, 2H), 3.46 (d, J = 9.9 Hz, 2H), 3.74 (d, J= 12.8 Hz, 2H), 4.74 (s, 2H), 6.83-6.84 (m, IH), 7.01 (d, J = 9.0 Hz, 2H), 7.16 (d, J= 3.7 Hz, IH), 7.34 (br s, IH), 7.72 (d, J= 9.0 Hz, 2H), 8.12 (br s, IH), 10.84 (br s, IH), 11.85 (br s, IH); MS (ES+): m/z 421 (M+H)⁺

Example 22: Preparation of 5-(2-Chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)thiophene-2- carboxylic acid (11)

11

[0152] To a solution of 8 (342 mg, 1.0 mmol) in dimethoxyethane (DME, 10 niL) was added a solution of 2-carboxythiophen-5-yl-5-boronic acid (172 mg, 1.0 mmol) in EtOH (5 mL), 2.0 M Na₂CO₃ (2 mL), and tetrakis(triphenylphosphine)palladium (0) (Pd(PPh₃ )₄, 115 mg, 0.1 mmol). The reaction mixture was heated at 110 ⁰C for 20 min under μ-wave. The hot solution was filtered and the solid was washed with EtOAc. The filtrate was washed with brine (50 mL). The aqueous was extracted with EtOAc (3 x 30 mL). Combined organic layer was dried (Na₂SO₄). The solvent was removed in vacuo. The residue was added MeOH and sonicated. The solid was collected by filtration. The title compound (360 mg, 83%) was afforded as a yellow solid.

Example 23: Preparation of 5-(2-Chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)thiophene-2- carboxamide (12)

12

[0153] A solution of compound 11 (360 mg, 0.83 mmol) in thioneyl chloride (20 mL) was heated at reflux overnight. The excess thioneyl chloride was removed in vacuo. The residue was added NH₃-H₂O (100 niL) and heated under reflux overnight. The solid was collected by filtration. The title compound (110 mg, 31%) was obtained as a brown solid.

Example 24: Preparation of 5-(2-(4-Morpholinophenylamino)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)thiophene-2-carboxamide (13)

13

[0154] To a suspension of compound 12 (110 mg, 0.25 mmol) in ra-BuOH (15 mL) was added 4-morpholinobenzenamine (91 mg, 0.5 mmol). The reaction mixture was heated at 180 ⁰C for 3 h under μ-wave. The solvent was removed. The crude product was purified by using HPLC. The HPLC fractions containing product were combined and neutralized with saturated NaHCO₃ (50 mL). The free base was extracted with EtOAc (2 x 50 mL). The organic layers were combined and dried (Na₂SO₄). The solvent was removed in vacuo and the residue was used for next step.

Example 25: Preparation of 5-(2-(4-Moφholinophenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)thiophene-2-carboxamide

[0155] The compound 13 was treated with tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 5 rnL, 5 mmol). The mixture was heated under reflux for 20 min. The solvent was removed in vacuo and the residue was dissolved in EtOAc (50 mL). The solution was washed with saturated NaHCO₃ (2 x 50 mL). The crude product was purified by using HPLC. The HPLC fractions containing product were combined and neutralized with saturated NaHCO₃ (50 mL). The free base was extracted with EtOAc (2 x 100 mL). The organic layers were combined and dried (Na₂SO₄). The solvent was removed in vacuo. The title compound (19 mg, 18%) was afforded as a yellow solid.

[0156] ¹H NMR (500 MHz, DMSO-d₆): δ 3.04 (t, J = 4.7 Hz, 4H), 3.74 (t, J = 4.7 Hz, 4H), 6.84-6.85 (m, IH), 6.90 (d, J = 9.2 Hz, 2H), 7.28-7.29 (m, IH), 7.54 (br s, IH), 7.72 (d, J = 9.2 Hz, 2H), 7.84 (d, J = 4.0 Hz, IH), 8.03 (d, J = 4.0 Hz, IH), 8.11 (br s, IH), 9.00 (s, IH), 11.61 (s, IH); MS (ES+): m/z 421 (M+H)⁺

Example 26: Preparation of [4-(5-Methyl-thiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-[4- (piperidine-4- sulf onyl) -phenyl] - amine

[0157] A mixture of 3 (0.12 g, 0.48 mmol), 4-(4-amino-benzenesulfonyl)-piperidine-l- carboxylic acid tert-butyl ester (0.205 g, 0.602 mmol), Pd₂(dba)₃ (0.044 g, 0.048 mmol), Xantphos (0.056 g, 0.1 mmol) and cesium carbonate (0.471 g, 1.45 mmol) were suspended in dioxane (4 mL) and microwaved at 160° C for 15 min. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and concentrated in vacuo. This was then purified by silica gel flash chromatography and the resulting residue treated with 20% TFA in DCM followed by solvent evaporation. HPLC purification afforded the title compound (0.022 g, 10%).

[0158] ¹H NMR (500 MHz, DMSOd₆): δ 1.68-1.77 (m, 2H), 2.01-2.04 (m, 2H), 2.57 (s, 3H), 2.85 (q, J = 12 Hz, 2H), 3.31 (d, J = 12.6 Hz, 2H), 3.49 (tt, J = 11.7, 3.8 Hz, IH), 6.87- 6.89 (m, IH), 7.01(d, J = 3.7 Hz, IH), 7.38-7.39 (m, IH), 7.72 (d, J= 8.9 Hz, 2H), 7.96 (d, J = 3.7 Hz, IH), 8.19 (d, J = 8.9 Hz, 2H), 8.65-8.67 (m, IH), 9.27-9.29 (m, IH), 9.99 (s, IH), 11.8 (s, IH) MS (ES+): m/z 454 (M+H)⁺

Example 27: Preparation of [4-(4-Methyl-thiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-(3- pyrrolidin- 1 -ylmethyl-phenyl)-amine

[0159] A mixture of 1 (0.138 g, 0.55 mmol), 3-pyrrolidin-l-ylmethyl-phenylamine (0.127 g, 0.72 mmol), Pd₂(dba)₃ (0.051 g, 0.06 mmol), tri-te/t-butyl-phosphine (IM in toluene, 0.111 mL, 0.111 mmol) and potassium tert-butoxide (0.31 g, 2.8 mmol) were suspended in dioxane (2 mL) and DMF (2 mL) and microwaved at 160° C for 30 min. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture diluted with ethyl acetate (10 mL), filtered and concentrated in vacuo. ΗPLC purification afforded the title compound (0.022 g, 10%).

[0160] ¹H NMR (500 MHz, DMSOd₆): δ 1.68-1.70 (m, 4H), 2.33 (s, 3H), 2.41-2.45 (m, 4H), 3.56 (s, 2H), 6.83-6.85 (m, 2H), 7.19 (t, J = 7.8 Hz, IH), 7.28-7.29 (m, IH), 7.39 (s, IH), 7.77 (d, J = 8 Hz, IH), 7.85 (s, IH), 7.91 (s, IH), 9.14 (s, IH), 11.6 (s, IH) MS (ES+): m/z 390 (M+H)⁺ Example 28: Preparation of [4-(4-Methyl-thiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-(3- morpholin-4-ylmethyl-phenyl)-amine

[0161] A mixture of 1 (0.172 g, 0.69 mmol), 3-morpholin-4-ylmethyl-phenylamine (0.17 g, 0.97 mmol), Pd₂(dba)₃ (0.063 g, 0.07 mmol), tri-tert-butyl-phosphine (IM in toluene, 0.138 mL, 0.138 mmol) and potassium tert-butoxide (0.387 g, 3.45 mmol) were suspended in dioxane (2 mL) and DMF (2 mL) and microwaved at 160° C for 30 min. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture diluted with ethyl acetate (10 mL), filtered and concentrated in vacuo. ΗPLC purification afforded the title compound (0.022 g, 10%).

[0162] ¹H NMR (500 MHz, DMSOd₆): δ 2.33 (s, 3H), 2.38 (br s, 4H), 3.45 (s, 2H), 3.57- 3.59 (m, 4H), 6.84-6.86 (m, 2H), 7.21 (t, J = 7.8 Hz, IH), 7.29-7.30 (m, IH), 7.39 (s, IH), 7.79 (d, J = 8 Hz, IH), 7.87 (s, IH), 7.92 (s, IH), 9.17 (s, IH), 11.6 (s, IH) MS (ES+): m/z 406 (M+H)⁺

Example 29: Preparation of 4-(4-Methylthiophen-2-yl)-N-[4-(moφholin-4-ylmethyl)phenyl]- 7H-pyrrolo[2,3-d]pyrimidin-2-amine

[0163] A mixture of 9 (0.1 g, 0.25 mmol), 4-morpholin-4-ylmethylphenylamine (0.058 g, 0.3 mmol), palladium acetate (5.6 mg (0.025 mmol), tri-te/t-butylphosphine (O.Olg, 0.05 mmol), triethylamine (0.25 g, 2.5 mmol) in dimethyl formamide (2 mL) was heated at 150 ⁰C for 30 min in a microwave reactor. Tetrabutyl ammonium fluoride (0.65 g, 2.5 mmol) in tetrahydrofuran (1 niL) was added and stirred at room temperature for 12 h. The reaction mixture was filtered, concentrated and purified by high performance liquid chromatography (C-18 column, water-acetonitrile) to afford the title compound (18 mg, 18%) as pale yellow solid.

[0164] ¹H NMR (500 MHz, DMSOd₆): δ 2.33 (s, 3H), 2.24 (br s, 3H), 3.39 (s, 3H), 3.57 (t,

J = 4.5 Hz, 4H), 6.85 (dd, J = 3.4, 1.8 Hz, IH), 7.18 (d, J = 8.6 Hz, 2H), 7.28 (dd, J = 3.5, 2.4

Hz, IH), 7.39 (s, IH), 7.84 (d, J = 8.6 Hz, 2H), 7.91 (d, J = 0.9 Hz, IH), 9.18 (s, IH), 11.60 (s,

IH)

MS (ES+): m/z 406 (M+H)⁺

Example 30: Preparation of N-{4-[(2-Methyl-lH-imidazol-l-yl)methyl]phenyl}-4-(4- methylthiophen-2-yl)-7H-pyrrolo[2,3-J]pyrimidin-2-amine

[0165] A mixture of 9 (0.1 g, 0.25 mmol), 4-(2-methylimidazol-l-ylmethyl)phenylamine (0.056 g, 0.3 mmol), palladium acetate (5.6 mg (0.025 mmol), tri-te/t-butylphosphine (O.Olg, 0.05 mmol), triethylamine (0.25 g, 2.5 mmol) in dimethyl formamide (2 mL) was heated at 150⁰C for 30 min in a microwave reactor. Tetrabutyl ammonium fluoride (0.65 g, 2.5 mmol) in tetrahydrofuran (1 mL) was added and heated in microwave reactor at 60 ⁰C for 30 min. The reaction mixture was filtered, concentrated and purified by high performance liquid chromatography (C-18 column, water-acetonitrile) to afford the title compound (17 mg, 17%) as pale yellow solid.

[0166] ¹H NMR (500 MHz, DMSOd₆): δ 2.27 (s, 3H), 2.32 (s, 3H), 5.06 (s, 2H), 6.78 (d, J = 1.3 Hz, IH), 6.85 (dd, J = 3.7, 1.8 Hz, IH), 7.11 (d, J= 8.6 Hz, 2H), 7.14 (d, J= 1.3 Hz, IH), 7.29 (dd, J = 3.6, 2.2 Hz, IH), 7.39 (t, J= 1.1 Hz, IH), 7.87 (d, J= 8.7 Hz, 2H), 7.91 (d, J = 1.0 Hz, IH), 9.26 (s, IH), 11.61 (s, IH) MS (ES+): m/z 401 (M+H)⁺

Example 31: Preparation of 4-(4-Methylthiophen-2-yl)-N-[4-(2-moφholin-4-ylethyl)phenyl]- 7H-pyrrolo[2,3-d]pyrimidin-2-amine

[0167] A mixture of 9 (0.1 g, 0.25 mmol), 4-(2-morpholin-4-yl-ethyl)aniline (0.062 mg, 0.3 mmol), palladium acetate (5.6 mg, 0.025 mmol), tri-tert-butylphosphine (O.Olg, 0.05 mmol), triethylamine (0.25 g, 2.5 mmol) in dimethyl formamide (2 mL) was heated at 150 ⁰C for 30 min in a microwave reactor. Tetrabutyl ammonium fluoride (0.65 g, 2.5 mmol) in tetrahydrofuran (1 mL) was added and heated in microwave reactor at 60 ⁰C for 30 min. The reaction mixture was filtered, concentrated and purified by high performance liquid chromatography (C-18 column, water-acetonitrile) to afford the title compound (19 mg, 18%) as pale yellow solid.

[0168] ¹H NMR (500 MHz, DMSOd₆): δ 2.32 (s, 3H), 2.43 (br s, 4H), 2.68 (t, J = 7.9 Hz, 2H), 3.30 (br s, 2H), 3.58 (br s, 4H), 6.84 (dd, J = 3.6, 1.7 Hz, IH), 7.12 (d, J = 8.5 Hz, 2H), 7.27 (dd, J = 3.5, 2.3 Hz, IH), 7.38 (d, J = 0.9 Hz, IH), 7.78 (d, J = 8.5 Hz, 2H), 7.91 (s, IH), 9.10 (s, IH), 11.59 (s, IH) MS (ES+): m/z 420 (M+H)⁺

Example 32: Preparation of N-(6-(4-Methylpiperazin-l-yl)pyridin-3-yl)-4-(4-methylthiophen- 2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine

[0169] A mixture of 9 (0.10 g, 0.38 mmol), 6-(4-methylpiperazin- l-yl)pyridin-3-amine (0.11 g, 0.46 mmol), Pd(OAc)₂ (30 mg, 0.033 mmol), tri-te/t-butylphosphine (35 mg, 0.06 mmol) and triethyl amine (0.25 g, 0.77 mmol) in DMF (3/1, 4 mL) was sealed in a microwave reaction vial and heated in microwave at 160 ⁰C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The fractions containing the desired product were combined and poured into saturated NaHCO₃ solution (30 mL). The aqueous mixture was extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated to give N-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)-4-(4-methylthiophen-2-yl)-7- tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine (36 mg) as yellow solid . The solid was dissolved in methanol (5 mL) and treated with sodium carbonate (50 mg; 0.47 mmol) at 100 ⁰C for 10 min. The solids were removed through filtration and the residue was purified using prep TLC to give the product as a brown solid (8 mg, 10%).

[0170] ¹H NMR (500 MHz, DMSO-d₆): δ 2.21, 2.31 (2s, 3H each), 2.24 (t, J = 5.0, 4H), 3.38 (t, J = 5, 4H), 6.80-6.85 (m, 2H), 7.23-7.26 (m, IH), 7.37 (s, IH), 8.00 (dd, J= 11.7, 2.7 Hz, IH), 8.60 (d, J = 2.7 Hz, IH), 8.94 (s, IH), 11.55 (br s, IH) MS (ES+): m/z 406(M+H)⁺

Example 33: Preparation of N-[4-(lH-Imidazol-l-yl)phenyl]-4-(4-methylthiophen-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine

[0171] 5 niL microwave vial was charged with 9 (404 mg, 1.0 mmol), 4-(lH-imidazol-l- yl)aniline (318 mg, 2.0 mmol), Pd(OAc)₂ (45 mg, 0.2 mmol), anhydrous DMF (4 mL), Et₃N (1.4 mL, 10.0 mmol) and 1.0 M solution of P(^-Bu)₃ (0.4 mL, 0.4 mmol). The reaction mixture was purged with argon gas for 5 min, and then the vial was sealed and irradiated in a microwave (Initiator, Biotage) at 160 ⁰C for 20 min. After cooling to room temperature, the reaction mixture was filtered through 0.2 u syringe filter and purified by reverse-phase preparative ΗPLC in CΗ₃CN/Η₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and partitioned between EtOAc (50 mL) and saturated aqueous NaHCO₃ (50 mL). The organic layer was washed with brine (1 x 30 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the Ts- protected compound as a yellow solid (130 mg, 25%). To this solid was added 6 mL of 1.0 M solution of TBAF in THF. The resulting solution was brought to reflux and refluxed for 20 min. The formed dark-red solution was diluted with EtOAc (100 mL) and extensively washed with saturated aqueous NaHCO₃ (5 x 50 mL). Then EtOAc layer was washed with brine (I x 30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was re- dissolved in 2 mL of DMF and purified by reverse-phase preparative HPLC in CH₃CN/H₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and partitioned between EtOAc (50 mL) and saturated aqueous NaHCO₃ (50 mL). The organic layer was washed with brine (1 x 30 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title product as a yellow solid (35 mg, 9% overall yield).

[0172] ¹H NMR (500 MHz, DMSO-d₆): δ 2.33 (s, 3H), 6.88 (d, J = 3.6 Hz, IH), 7.08 (s, IH), 7.32 (d, J = 3.7 Hz, IH), 7.40 (s, IH), 7.54 (d, J = 8.9 Hz, 2H), 7.68 (s, IH), 7.94 (s, IH), 8.05 (d, J = 8.9 Hz, 2H), 8.17 (s, IH), 9.43 (s, IH), 11.70 (s, IH) MS (ES+): m/z 373 (M+H)⁺

Example 34: Preparation of 2-Chloro-4-(thiophen-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine

(14)

14

[0173] A mixture of 8 (0.17 g, 0.50 mmol), thiophen-2-yl-2-boronic acid (80 mg, 0.62 mmol), Pd(PPh₃ )₄ (60 mg, 0.05 mmol) and sodium carbonate (0.16 g, 1.5 mmol) in anhydrous DMF (25 mL) was refluxed in a sealed tube at 150 ⁰C for 5 h. After cooling to room temperature, the cap was removed and the solvent was removed by rotovap. The crude product was then purified by silica gel column with hexanes and Et₂O as eluents to yield the title compound as a yellow solid (50 mg, 26%).

[0174] ¹H NMR (500 MHz, CDCl₃): δ 2.42 (s, 3H), 6.95 (d, J = 4.1 Hz, IH), 7.21 (dd, J = 5.0, 3.9 Hz, IH), 7.35 (d, J = 8.4 Hz, 2H), 7.62 (dd, J = 4.9, 0.8 Hz, IH), 7.76 (d, J = 4.0 Hz, IH), 7.94 (dd, J = 3.6, 0.9 Hz, IH), 8.13 (d, J = 8.5 Hz, 2H)

Example 35: Preparation of N-(4-Methoxyphenyl)-4-(thiophen-2-yl)-7-tosyl-7H-pyrrolo[2,3- d] pyrimidin-2- amine (15)

[0175] A mixture of 14 (50 mg, 0.13 mmol), p-anisidine (20 mg, 0.15 mmol), Pd₂(dba)₃ (12 mg, 0.01 mmol), tri-tert-butylphosphine (25 mg, 0.12 mmol) and sodium tert-butoxide (25 mg, 0.26 mmol) in anhydrous DMF (5 mL) was refluxed in a sealed tube at 150 ⁰C for 3 h. After cooling to room temperature, the cap was removed and the solvent was removed by rotovap. The crude product was then purified by silica gel column with hexanes to Et₂O as eluents to yield the title compound as a yellow solid (13 mg, 26%). [0176] ¹H NMR (500 MHz, CDCl₃): δ 2.35 (s, 3H), 3.86 (s, 3H), 6.82 (d, J = 4.2 Hz, IH), 6.98 (d, J = 7.0 Hz, 2H), 7.07 (br s), 7.10-7.25 (m, 3H), 7.48 (d, J = 4.4 Hz, IH), 7.53 (d, J = 6.0 Hz, IH), 7.69 (d, J= 8.0 Hz, 2H), 7.83 (d, J= 3.6 Hz, IH), 7.99 (d, J= 8.4 Hz, 2H)

Example 36: Preparation of N-(4-Methoxyphenyl)-4-(thiophen-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-amine

[0177] A mixture of 15 (13 mg, 0.03 mmol), and cesium carbonate (54 mg, 0.16 mmol) in methanol (10 mL) and TΗF (5 mL) was refluxed for 3 h. After cooling to room temperature, the solvent was removed by rotovap. The product was isolated by precipitating out from water (6 mg, 56%) to yield the title compound as a yellow solid.

[0178] ¹H NMR (500 MHz, CDCl₃): δ 3.82 (s, 3H), 6.73 (br s, IH), 6.91 -6.93 (m, 4H), 7.21 (dd, J = 4.8, 3.9 Hz, IH), 7.53 (d, J = 4.8 Hz, IH), 7.59 (d, J = 8.9 Hz, 2H), 7.93 (d, J = 3.2 Hz, IH), 8.81 (br s)

Example 37: Preparation of N-(4-(2-(Pyrrolidin-l-yl)ethoxy)phenyl)-4-(thiophen-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine

[0179] A mixture of 14 (50 mg, 0.13 mmol), 4-(2-(pyrrolidin-l-yl)ethoxy)benzenamine (32 mg, 0.16 mmol), Pd₂(dba)₃ (12 mg, 0.01 mmol), tri-te/t-butylphosphine (25 mg, 0.12 mmol) and cesium carbonate (0.13 g, 0.4 mmol) in anhydrous DMF (10 mL) was refluxed in a sealed tube at 150 ⁰C for 8 h. After cooling to room temperature, the cap was removed and the solvent was removed by rotovap. The crude product was then purified by silica gel column with 20% CΗ₃OΗ/CΗC1₃ as an eluent the title compound as a yellow solid (7 mg, 14%). [0180] ¹H NMR (500 MHz, CDCl₃): δ 1.68 (br s, 4H), 2.66 (br s, 4H), 2.92 (br s, 2H), 4.13 (br s, 2H), 6.74 (br s, IH), 6.70-7.10 (m, 4H), 7.15-7.20 (m, IH), 7.45-7.60 (m, 3H), 7.93 (s, IH), 8.71 (br s, IH) MS (ES+): m/z 406 (M+H)⁺

Example 38: Preparation of N-(3-Morpholinopropyl)-4-(thiophen-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-amine

[0181] A mixture of 14 (50 mg, 0.13 mmol) and 3-morpholinopropan-l -amine (90 mg, 0.64 mmol) in a sealed tube was heated at 90 ⁰C for 8 h. After cooling to room temperature, the cap was removed and the solvent was removed by rotovap. The crude product was then purified by silica gel column with 10% CΗ₃OΗ/CΗCI₃ as an eluent to yield the Ts-protected intermediate as a yellow solid. The above intermediate and cesium carbonate (54 mg, 0.16 mmol) in methanol (10 mL) and THF (5 mL) was refluxed for 3 h. After cooling to room temperature, the solvent was removed by rotovap. The crude product was then purified by silica gel column with 10% CH₃OH/CHCI₃ as an eluent to yield the title compound as a yellow solid (16 mg, 36%).

[0182] ¹H NMR (500 MHz, CDCl₃): δ 1.82-1.90 (m, 2H), 2.49 (br s, 4H), 2.53 (t, J = 6.9 Hz, 2H), 3.57 (dd, J = 10.7, 6.1 Hz, 2H), 3.77 (t, J = 4.7 Hz, 4H), 5.72 (br s, IH), 6.70 (dd, J = 3.6, 1.8 Hz, IH), 7.0 (dd, J= 3.7, 2.1 Hz, IH), 7.19 (dd, J = 5.0, 3.7 Hz, IH), 7.50 (dd, J= 4.9, 0.8 Hz, IH), 7.90 (dd, J = 3.5, 0.7 Hz, IH), 9.29 (br s, IH) MS (ES+): m/z 344 (M+H)⁺

Example 39: Preparation of 2-(4-Methoxyphenoxy)-4-(thiophen-2-yl)-7H-pyrrolo[2,3- d]pyrimidine

[0183] A mixture of 14 (50 mg, 0.13 mmol), 4-methoxyphenol (50 mg, 0.40 mmol), cesium carbonate (83 mg, 0.26 mmol) in acetone (20 mL) was refluxed for 4 h. After cooling to room temperature, the solvent was removed by rotovap. The crude product was dissolved in chloroform (30 mL), washed by 2 M NaOH (3 x 15 mL) to remove the excess of the A- methoxyphenol. The organic solution was dried over MgSO₄ and purified by silica gel column with 5% CH₃OH/CHCI₃ as an eluent to yield the title compound as a yellow solid (12 mg, 26%).

[0184] ¹H NMR (500 MHz, CDCl₃): δ 3.78 (s, 3H), 6.90-7.00 (m, 3H), 7.17 (d, J = 4.5 Hz, 2H), 7.29 (dd, J = 5.1, 3.8 Hz, IH), 7.19 (dd, J= 5.0, 3.7 Hz, IH), 7.44 (dd, J = 3.6, 2.2 Hz, IH), 7.84 (dd, J = 5.1, 1.0 Hz, IH), 8.12 (dd, J= 3.7, 1.0 Hz, IH), 12.1 (s, IH) MS (ES+): m/z 324 (M+H)⁺

Example 40: Preparation of 5-{2-[4-(2-Pyrrolidin-l-yl-ethoxy)-phenylamino]-7H-pyrrolo[2,3- d]pyrimidin-4-yl } -thiophene-2-carbaldehyde (16)

16

[0185] To a microwave reaction tube was charged with 7 (0.50 g, 1.4 mmol), 5- formylthiophene-2-boronic acid (0.30 g, 1.9 mmol) and Pd(PPh₃ )₄ (0.15 g, 0.13 mmol). DMF (5 mL) was added to the above mixture followed by aqueous sodium carbonate (2 M; 1.5 mL, 3.0 mmol). The reaction tube was sealed and the suspension irradiated with microwave at 140 ⁰C for 20 min. After cooling to room temperature, the mixture was filtered, the filtered solid washed with DCM and the filtrate concentrated. The crude product was purified by column chromatography on silica gel (DCM to 30% MeOH/DCM) to afford the title compound (0.23 g, 38%) as a red solid.

MS (ES+): m/z 434 (M+H)⁺

Example 41: Preparation of 5-(5-{2-[4-(2-Pyrrolidin-l-yl-ethoxy)-phenylamino]-7H- pyrrolo[2,3-(i]pyrimidin-4-yl}-thiophen-2-ylmethylene)-thiazolidine-2,4-dione

[0186] A microwave vial was charged with 16 (0.14 g, 0.32 mmol), thiazolidine-2,4-dione (60 mg, 0.51 mmol), and Cs₂CO₃ (0.16 g, 0.49 mmol) in ethanol (4 mL). The reaction mixture was heated for 40 min at 140 ⁰C in a Biotage microwave reactor. The resulting reaction mixture was concentrated and the residue triturated in water. The resulting solid was filtered and purified by ΗPLC. The fractions were combined and poured into saturated NaHCO₃ solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the residue triturated in a mixture of EtOAc/hexanes (1/3, 20 mL). After filtration, the title compound was obtained as a red solid (20 mg, 12%).

[0187] ¹H NMR (500 MHz, CDCl₃): δ 1.80-1.90 (m, 4H), 3.00-3.20 (m, 4H), 4.20-4.28 (m, 2H), 6.85 (dd, J = 3.5, 1.7 Hz, IH), 6.95 (d, J = 9.0 Hz, 2H), 7.27 (t, J = 2.9 Hz, IH), 7.49 (d, J = 4.0 Hz, IH), 7.60 (s, IH), 7.83 (d, J = 9.0 Hz, 2H), 8.07 (d, J = 4.0 Hz, IH), 9.11 (s, IH), 11.60 (s, IH) MS (ES+): m/z 533 (M+H)⁺

Example 42: Preparation of fert-Butyl[(lZ)-[(fert-butoxycarbonyl)amino]{ [4-(4- methylpiperazin- 1 -yl)phenyl] amino } methylidene] carbamate (17)

17

[0188] A mixture of (fer?-butoxycarbonylimino-pyrazol-l-yl-methyl)-carbamic acid tert- butyl ester (3.1 g, 10.0 mmol) and 4-(4-methylpiperazin-l-yl)benzenamine (1.9 g, 10.0 mmol) in DMF (10 rnL) was stirred at room temperature for 17 h. The reaction mixture was concentrated and the residue taken in water (50 mL). The resulting solid was filtered, washed with water and dried under high vacuum to afford the title compound as an off white solid. The material was used in the next step without purification.

Example 43: Preparation of (4-(4-Methylpiperazin-l-yl)phenyl)guanidine TFA salt (18)

18

[0189] A solution of 17 in 50% TFA/DCM (10 mL) was stirred at room temperature for 17 h. The solution was concentrated to afford the title compound (4.6 g, 99%), which was used in the next step without purification.

Example 44: Preparation of 2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-ol (19)

19 [0190] To a microwave reaction tube was charged with 18 (2.3 g, 5.0 mmol), 2-cyano-4,4- diethoxy-butyric acid ethyl ester (2.3 g, 10.0 mmol) and NaOMe (25% by wt in MeOH; 12 mL) in EtOH (5 mL). The reaction tube was sealed and the solution irradiated with microwave at 160 ⁰C for 30 min. After cooling to room temperature, the mixture was concentrated. The residue was taken up in water (10 mL) and the pH adjusted to 1 with 6M of HCl. The resulting solution was stirred at room temperature for 25 min and then the pH adjusted to 9 with concentrated 10% NaOH. The resulting solid was filtered, washed with water and dried under high vacuum to afford the title compound as a brown solid (1.6 g, 96%). The material was used in the next step without purification.

Example 45: Preparation of 4-Chloro-N-(4-(4-methylpiperazin-l-yl)phenyl)-7H-pyrrolo[2,3- d] pyrimidin-2- amine (9)

20

[0191] A solution of 19 (1.6 g, 4.8 mmol) in POCl₃ (5 mL) was heated at 120 ⁰C for 20 min. After cooling to room temperature, the excess POCl₃ was removed in vacuo. The resulting dark residue was added ice water slowly and the pΗ was adjusted to 9-10 with 10% NaOH. The resulting solid was filtered, washed with water and dried under high vacuum to afford the title compound as a brown solid (1.1 g, 69%). The material was used in the next step without purification.

Example 46: Preparation of 5-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)thiophene-2-carbaldehyde (21)

21

[0192] To a solution of 20 (172 mg, 0.5 mmol) in dimethoxyethane (DME, 10 niL) was added a solution of 5-cyanothiophen-2-yl-2-boronic acid (80 mg, 0.55 mmol) in EtOH (5 mL), 2.0 M Na₂CO₃ (1.0 mL), and tetrakis(triphenylphosphine)palladium (0) (Pd(PPh₃ )₄, 58 mg, 0.05 mmol). The reaction mixture was heated at 110 ⁰C for 20 min under μ-wave. The hot solution was filtered and the solid was washed with EtOAc. The filtrate was washed with brine (50 mL). The aqueous was extracted with EtOAc (3 x 30 mL). Combined organic layer was dried (Na₂SO₄). The solvent was removed in vacuo. The residue was added MeOH and sonicated. The solid was collected by filtration. The title compound was afforded as a yellow solid.

Example 47: Preparation of (Z)-5-((5-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)thiophen-2-yl)methylene)thiazolidine-2,4-dione

[0193] To a solution of 21 (0.25 mmol) in EtOH (10 mL) was added thiazolidine-2,4-dione (TZD, 59 mg, 0.5 mmol) and 'BuOK (112 mg, 1.0 mmol). The reaction mixture was heated at 120 ⁰C for 20 min under μ-wave. The solvent was removed in vacuo and the residue was suspended in H₂O-EtOAc. The organic layer was separated. The aqueous was stood overnight. The solid was collected and washed with water and then MeOH. The solid was dried in air and the title compound (20 mg, 16%) was afforded as a black solid.

[0194] ¹H NMR (500 MHz, DMSO-d₆): δ 2.70 (br s, 3H), 3.14 (br s, 8H), 6.85 (s, IH), 6.93 (d, J = 9.0 Hz, 2H), 7.26 (s, IH), 7.54 (d, J = 3.9 Hz, IH), 7.68 (s, IH), 7.75 (d, J = 9.0 Hz, 2H), 8.08 (d, J = 3.9 Hz, IH), 9.02 (s, IH), 8.12 (br s, IH), 11.58 (s, IH); MS (ES+): m/z 518 (M+H)⁺ Example 48: Preparation of 5-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)thiophene-2-carbonitrile

[0195] To a solution of 20 (86 mg, 0.25 mmol) in dimethoxyethane (DME, 10 rnL) was added a solution of 5-formylthiophen-2-yl-2-boronic acid (43 mg, 0.28 mmol) in EtOH (5 mL), 2.0 M Na₂CO₃ (0.5 mL), and tetrakis(triphenylphosphine)palladium (0) (Pd(PPh₃ )₄, 23 mg, 0.02 mmol). The reaction mixture was heated at 110 ⁰C for 20 min under μ-wave. The hot solution was filtered and the solid was washed with EtOAc. The organic solution was separated and the aqueous was extracted with EtOAc (2 x 50 mL). The combined organic layer was dried (Na₂SO₄). The solvent was removed in vacuo. The crude product was purified by using ΗPLC. The ΗPLC fractions containing product were combined and neutralized with saturated NaHCO₃ (50 mL). The free base was extracted with EtOAc (2 x 100 mL). The organic layers were combined and dried (Na₂SO₄). The solvent was removed in vacuo. The residue was dissolved in MeOH (2 mL) and 4.0 M HCl solution (0.3 mL, 1.2 mmol) in dioxane was added. The solution was stirred for 5 min at room temperature and then solvent was removed in vacuo. The residue was dissolved in MeOH (1 mL) and anhydrous Et₂O (20 mL) was added. The solid was collected by centrifuging. The title compound (21 mg, 9%) was afforded as a yellow solid.

[0196] ¹H NMR (500 MHz, DMSO-d₆): δ 2.81 (d, J= 4.4 Hz, 3H), 3.05 (t, J= 11.9 Hz, 2H), 3.14-3.20 (m, 2H), 3.48 (d, J = 11.3 Hz, 2H), 3.73 (d, J = 12.8 Hz, 2H), 6.91-6.92 (m, IH), 7.01 (d, J = 9.1 Hz, 2H), 7.14 (s, IH), 7.24 (s, IH), 7.34 (s, IH), 7.37-7.38 (m, IH), 7.73 (d, J = 9.1 Hz, 2H), 8.10 (d, J = 4.2 Hz, IH), 8.18 (d, J = 4.2 Hz, IH), 9.21 (br s, IH), 10.76 (br s, IH), 11.77 (s, IH); MS (ES+): m/z 416 (M+H)⁺

Example 49: Preparation of 5-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)thiophene-2-carboxylic acid (22)

22

[0197] To a solution of 20 (430 mg, 1.25 mmol) in dimethoxyethane (DME, 10 niL) was added a solution of 2-carboxythiophen-5-yl-5-boronic acid (237 mg, 1.38 mmol) in EtOH (5 mL), 2.0 M Na₂CO₃ (2.5 mL), and tetrakis(triphenylphosphine)palladium (0) (Pd(PPh₃ )₄, 116 mg, 0.1 mmol). The reaction mixture was heated at 110 ⁰C for 20 min under μ-wave. The hot solution was filtered and the solid was washed with EtOAc. The filtrate was added with water (100 mL) and the organic solution was separated. The aqueous was extracted with EtOAc (2 x 50 mL). The aqueous that contains product was concentrated. The solid was collected by filtration and dried. The title compound (296 mg, 55%) was afforded as a yellow solid.

Example 50: Preparation of (5-(2-(4-(4-methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)thiophen-2-yl)(morpholino)methanone

[0198] To a solution of 22 (126 mg, 0.29 mmol) in CH₂Cl₂ (10 mL) was added 2-chloro- 4,6-dimethoxy-l,3,5-triazine (CDMT, 61 mg, 0.35 mmol) and 4-methylmorpholine (NMM, 0.06 mL, 0.7 mmol). The reaction mixture was stirred at room temperature for 2 h. Morpholine (0.5 mL, 3.8 mmol) was added into above solution. The reaction mixture was stirred at room temperature overnight. The saturated NaHCO₃ (100 mL) was added. The organic solution was separated and the aqueous was extracted with CH₂Cl₂ (2 x 50 mL). The combined organic layer was dried (Na₂SO₄). The solvent was removed in vacuo. The crude product was purified by using HPLC. The HPLC fractions containing product were combined and neutralized with saturated NaHCO₃ (50 rnL). The free base was extracted with EtOAc (2 x 100 rnL). The organic layers were combined and dried (Na₂SO₄). The solvent was removed in vacuo. The residue was dissolved in MeOH (2 mL) and 4.0 M HCl solution (0.3 mL, 1.2 mmol) in dioxane was added. The solution was stirred for 5 min at room temperature and then solvent was removed in vacuo. The residue was dissolved in MeOH (1 mL) and anhydrous Et₂O (20 mL) was added. The solid was collected by centrifuging. The title compound (64 mg, 41%) was afforded as a yellow solid.

[0199] ¹H NMR (500 MHz, DMSO-d₆): δ 2.81 (d, J = 4.4 Hz, 3H), 3.06 (t, J = 11.1 Hz, 2H), 3.15-3.21 (m, 2H), 3.49 (d, J = 11.8 Hz, 2H), 3.67-3.68 (m, 8H), 3.73 (d, J= 13.3 Hz, 2H), 6.85-6.86 (m, IH), 6.99 (d, / = 9.1 Hz, 2H), 7.33-7.34 (m, IH), 7.53 (d, J = 3.9 Hz, IH), 7.76 (d, J = 9.1 Hz, 2H), 8.05 (d, J = 3.9 Hz, IH), 9.22 (br s, IH), 10.73 (br s, IH), 11.73 (s, IH) MS (ES+): m/z 504 (M+H)⁺

Example 51: Preparation of 2-Chloro-4-(5-methyl-benzo[b]thiophen-2-yl)-7H-pyrrolo[2,3- d]pyrimidine (23)

23

[0200] To a microwave reaction tube was charged with 2,4-dichloro-7H-pyrrolo[2,3- d]pyrimidine (0.30 g, 1.6 mmol), boronic acid (0.40 g, 2.1 mmol) and Pd(PPh₃)₄ (0.15 g, 0.13 mmol). DMF (3 mL) was added followed by aqueous sodium carbonate (2 M; 1.5 mL, 3.0 mmol). The reaction tube was sealed and the suspension irradiated with microwave at 150 ⁰C for 15 min. After cooling to room temperature, the mixture was filtered and the filtrate concentrated. The residue was triturated in MeOH and the solid filtered to afford the title compound (0.32 g, 67%) as a brown solid. The material was used in the next step without purification.

Example 52: Preparation of [4-(5-Methyl-benzo[b]thiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin- 2-yl]-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-amine

[0201] A suspension of 23 (0.10 g, 0.33 mmol), 4-(2-pyrrolidin-l-yl-ethoxy)-phenylamine (0.10 g, 0.49 mmol), Pd₂(dba)₃ (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (2/1, 6 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 ⁰C for 30 min. After cooling to room temperature, the resulting mixture was filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by ΗPLC. The fractions were combined and poured into saturated NaHCO₃ solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a yellow solid (23 g, 15%).

[0202] ¹H NMR (500 MHz, DMSO-d₆): δ 1.70-1.80 (m, 4H), 2.46 (s, 3H), 2.60-2.80 (m, 4H), 2.90-3.05 (m, 2H), 4.10 (t, J = 5.3 Hz, 2H), 6.93 (d, J = 9.1 Hz, 2H), 6.97 (dd, J= 3.6, 1.7 Hz, IH), 7.28 (dd, J = 8.4, 1.3 Hz, IH), 7.34 (dd, J = 3.4, 2.4 Hz, IH), 7.80 (s, IH), 7.81 (d, J = 8.9 Hz, 2H), 7.92 (d, J = 8.2 Hz, IH), 8.37 (s, IH), 9.10 (s, IH), 11.7 (s, IH) MS (ES+): m/z 470 (M+H)⁺

Example 53: Preparation of [4-(5-Methyl-benzo[b]thiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin- 2-yl] -[4-(4-methyl-piperazin- 1 -ylmethyl)-phenyl] -amine

[0203] A suspension of 23 (0.10 g, 0.33 mmol), 4-(4-methyl-piperazin- 1-ylmethyl)- phenylamine (0.10 g, 0.49 mmol), Pd₂(dba)₃ (25 mg, 0.027 mmol), Xantphos (32 mg, 0.055 mmol) and cesium carbonate (0.22 g, 0.68 mmol) in dioxane (4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 ⁰C for 20 min. After cooling to room temperature, the resulting mixture was filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO₃ solution (25 mL). The combined aqueous layers were extracted with EtOAc (2 x 25 mL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the residue re- dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a yellow solid (10 g, 6%).

[0204] ¹H NMR (500 MHz, DMSO-d₆): δ 2.18 (s, 3H), 2.25-2.45 (m, 8H), 2.46 (s, 3H), 3.41 (s, 2H), 7.00 (dd, J = 3.6, 1.7 Hz, IH), 7.21 (d, J = 8.5 Hz, 2H), 7.29 (dd, J= 8.4, 1.3 Hz, IH), 7.38 (dd, J = 3.6, 2.3 Hz, IH), 7.81 (s, IH), 7.87 (d, J= 8.5 Hz, 2H), 7.94 (d, J= 8.3 Hz, IH), 8.39 (s, IH), 9.27 (s, IH), 11.7 (s, IH) MS (ES+): m/z 469 (M+H)⁺

Example 54: Preparation of 4-(Benzo[b]thiophen-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine

(24)

24 [0205] To a solution of 2,4-dichloro-7H-pyrrolo[2,3-<i]pyrimidine (376 mg, 2.0 mmol) in dimethoxyethane (DME, 10 niL) was added a solution of benzo[b]thiophen-2-yl-2-boronic acid (356 mg, 2.0 mmol) in EtOH (5 mL), 4.0 M Na₂CO₃ (2 mL), and tetrakis(triphenylphosphine)palladium (0) (Pd(PPh₃)₄, 230 mg, 0.2 mmol). The reaction mixture was heated at 110 ⁰C for 20 min under μ-wave. The hot solution was filtered and the solid was washed with EtOAc. The filtrate was washed with brine (50 mL). The aqueous was extracted with EtOAc (3 x 30 mL). Combined organic layer was dried (Na₂SO₄). The solvent was removed in vacuo. The residue was added MeOH and sonicated. The solid was collected by filtration. The title compound (380 mg, 67%) was afforded as a yellow solid.

Example 55: Preparation of 4-(Benzo[b]thiophen-2-yl)-N-(4-(4-methylpiperazin-l-yl)phenyl)- 7H-pyrrolo[2,3-d]pyrimidin-2-amine

[0206] To a solution of 24 (72 mg, 0.25 mmol) in 1,4-dioxane (10 mL) and DMF (5 mL) was added 4-(4-methylpiperazin-l-yl)benzenamine (52 mg, 0.27 mmol), KO'Bu (112 mg, 1.0 mmol), Pd₂(dba)₃ (20 mg, 0.02 mmol), and 1.0 M tri-te/t-butylphosphine in toluene (0.06 mL, 0.06 mmol). The reaction mixture was heated at 150 ⁰C for 20 min under μ-wave. The solid was filtered off and the filtrate was washed with brine (1 x 50 mL). The organic solution was separated and dried (Na₂SO₄). The solvent was removed in vacuo. The crude product was purified by using ΗPLC. The ΗPLC fractions containing product were combined and neutralized with saturated NaHCO₃ (50 mL). The free base was extracted with EtOAc (2 x

100 mL). The organic layers were combined and dried (Na₂SO₄). The solvent was removed in vacuo. The residue was dissolved in MeOH (2 mL) and 4.0 M HCl solution (0.2 mL, 0.8 mmol) in dioxane was added. The solution was stirred for 5 min at room temperature and then solvent was removed in vacuo. The residue was dissolved in MeOH (1 mL) and anhydrous Et₂O (20 mL) was added. The solid was collected by centrifuging. The title compound (39 mg, 33%) was afforded as a yellow solid. [0207] ¹H NMR (500 MHz, DMSO-d₆): δ 2.81 (s, 3H), 3.18-3.20 (m, 4H), 3.51 (d, J = 9.9 Hz, 2H), 3.75 (d, J = 10.2 Hz, 2H), 7.00-7.02 (m, IH), 7.07 (d, J = 8.9 Hz, 2H), 7.39-7.40 (m, IH), 7.44-7.49 (m, 2H), 7.81 (d, J= 8.9 Hz, 2H), 8.01-8.03 (m, IH), 8.06-8.08 (m, IH), 8.54 (s, IH), 9.40 (br s, IH), 11.21 (br s, IH), 11.85 (s, IH) MS (ES+): m/z 441 (M+H)⁺

Example 56: Preparation of 4-(Benzo[b]thiophen-2-yl)-N-(6-(4-methylpiperazin-l-yl)pyridin- 3-yl)-7H-pyrrolo-[2,3-J]pyrimidin-2-amine

[0208] To a solution of 24 (72 mg, 0.25 mmol) in 1,4-dioxane (10 rnL) and DMF (5 rnL) was added 6-(4-methylpiperazin-l-yl)pyridin-3-amine (53 mg, 0.27 mmol), KO'Bu (112 mg, 1.0 mmol), Pd₂(dba)₃ (20 mg, 0.02 mmol), and 1.0 M tri-te/t-butylphosphine in toluene (0.06 mL, 0.06 mmol). The reaction mixture was heated at 150 ⁰C for 20 min under μ-wave. The solid was filtered off and the filtrate was washed with brine (1 x 50 mL). The organic solution was separated and dried (Na₂SO₄). The solvent was removed in vacuo. The crude product was purified by using ΗPLC. The ΗPLC fractions containing product were combined and neutralized with saturated NaHCO₃ (50 mL). The free base was extracted with EtOAc (2 x

100 mL). The organic layers were combined and dried (Na₂SO₄). The solvent was removed in vacuo. The residue was dissolved in MeOH (2 mL) and 4.0 M HCl solution (0.2 mL, 0.8 mmol) in dioxane was added. The solution was stirred for 5 min at room temperature and then solvent was removed in vacuo. The residue was dissolved in MeOH (1 mL) and anhydrous Et₂O (20 mL) was added. The solid was collected by centrifuging. The title compound (21 mg, 17%) was afforded as a yellow solid.

[0209] ¹H NMR (500 MHz, DMSO-d₆): δ 2.81 (d, J= 4.0 Hz, 3H), 3.15-3.22 (m, 2H), 3.54 (d, J = 11.9 Hz, 4H), 4.43 (d, J = 13.9 Hz, 2H), 7.05-7.06 (m, IH), 7.37 (br s, IH), 7.44-7.49 (m, 3H), 8.03-806 (m, 2H), 8.33 (d, J = 8.6 Hz, IH), 8.55 (s, IH), 8.94 (s, IH), 9.60 (br s, IH), 11.34 (br s, IH), 11.88 (s, IH) MS (ES+): m/z 442 (M+H)⁺ Example 57: Preparation of N-(4-(2-(Pyrrolidin-l-yl)ethoxy)phenyl)-4-(benzo[b]thiophen-2- yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine

[0210] To a solution of 24 (72 mg, 0.25 mmol) in 1,4-dioxane (10 rnL) and DMF (5 rnL) was added 4-(2-(pyrrolidin-l-yl)ethoxy)benzenamine (52 mg, 0.25 mmol), KO'Bu (112 mg, 1.0 mmol), Pd₂(dba)₃ (20 mg, 0.02 mmol), and 1.0 M tri-te/t-butylphosphine in toluene (0.06 mL, 0.06 mmol). The reaction mixture was heated at 150 ⁰C for 20 min under μ-wave. The solid was filtered off and the filtrate was washed with brine (1 x 50 mL). The organic solution was separated and dried (Na₂SO₄). The solvent was removed in vacuo. The crude product was purified by using ΗPLC. The ΗPLC fractions containing product were combined and neutralized with saturated NaHCO₃ (50 mL). The free base was extracted with EtOAc (2 x 100 mL). The organic layers were combined and dried (Na₂SO₄). The solvent was removed in vacuo. The residue was dissolved in MeOH (2 mL) and 4.0 M HCl solution (0.2 mL, 0.8 mmol) in dioxane was added. The solution was stirred for 5 min at room temperature and then solvent was removed in vacuo. The residue was dissolved in MeOH (1 mL) and anhydrous Et₂O (20 mL) was added. The solid was collected by centrifuging. The title compound (8 mg, 6%) was afforded as an orange solid.

[0211] ¹H NMR (500 MHz, DMSO-d₆): δ 1.87-1.92 (m, 2H), 1.99-2.05 (m, 2H), 3.07-3.13 (m, 2H), 3.56-3.60 (m, 4H), 4.35 (t, J = 5.1 Hz, 2H), 7.01 (d, J = 8.9 Hz, 2H), 7.01 (s, IH), 7.36-7.37 (m, IH), 7.44-7.46 (m, 2H), 7.84 (d, J = 8.9 Hz, 2H), 8.01-8.02 (m, IH), 8.04-8.06 (m, IH), 8.48 (s, IH), 9.20 (br s, IH), 11.00 (br s, IH), 11.75 (s, IH); MS (ES+): m/z 456 (M+H)⁺

Example 58 Preparation of [4-(4-Methyl-thiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-[4- (2-pyrrolidin- 1 -yl-ethoxy)-phenyl] -amine

[0212] To a microwave reaction tube was charged with 7 (0.10 g, 0.28 mmol), A- methylthiophene-2-boronic acid (50 mg, 0.35 mmol) and Pd(PPlIs)₄ (30 mg, 0.026 mmol). DMF (4 mL) was added to the above mixture followed by 2 M of sodium carbonate (0.5 mL). The reaction tube was sealed and the suspension irradiated with microwave at 140 ⁰C for 20 min. After cooling to room temperature, the mixture was filtered, the filtered solid washed with DCM and the filtrate concentrated. The crude product was purified by HPLC, the fractions combined and poured into saturated NaHCO₃ solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a yellow solid (22 mg, 19%).

[0213] ¹H NMR (500 MHz, DMSO-J₆): δ 1.65-1.73 (m, 4H), 2.32 (s, 3H), 2.50-2.65 (m, 4H), 2.79-2.89 (m, 2H), 4.04 (t, J = 5.9 Hz, 2H), 6.82 (dd, J = 3.7, 1.8 Hz, IH), 6.88 (d, J = 9.1 Hz, 2H), 7.24 (dd, J = 3.6, 2.3 Hz, IH), 7.37 (t, J = 1.2 Hz, IH), 7.77 (d, J = 9.1 Hz, 2H), 7.89 (d, J = 1.1 Hz, IH), 8.99 (s, IH), 11.55 (s, IH) MS (ES+): m/z 420 (M+H)⁺

Example 59 [4-(5-Methyl-thiophen-2-yl)-7H-pyrrolo[2,3-<i]pyrimidin-2-yl]-[4-(2-pyrrolidin- 1 -yl-ethoxy)-phenyl] -amine

[0214] To a microwave reaction tube was charged with 7 (0.10 g, 0.28 mmol), 5- methylthiophene-2-boronic acid (50 mg, 0.35 mmol) and Pd(PPh₃)₄ (30 mg, 0.026 mmol). DMF (4 niL) was added to the above mixture followed by 2 M of sodium carbonate (0.5 mL). The reaction tube was sealed and the suspension irradiated with microwave at 140 ⁰C for 20 min. After cooling to room temperature, the mixture was filtered, the filtered solid washed with DCM and the filtrate concentrated. The crude product was purified by HPLC, the fractions combined and poured into saturated NaHCO₃ solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a yellow solid (18 mg, 15%).

[0215] ¹H NMR (500 MHz, DMSO-J₆): δ 1.65-1.73 (m, 4H), 2.50-2.60 (m, 4H), 2.54 (s, 3H), 2.79 (t, J = 5.8 Hz, 2H), 4.03 (t, J = 6.0 Hz, 2H), 6.77 (dd, J = 3.6, 1.7 Hz, IH), 6.88 (d, J = 9.0 Hz, 2H), 6.97 (dd, J = 3.8, 1.0 Hz, IH), 7.22 (dd, J= 3.6, 2.3 Hz, IH), 7.76 (d, J = 9.1 Hz, 2H), 7.86 (d, J = 3.7 Hz, IH), 8.96 (s, IH), 11.53 (s, IH) MS (ES+): m/z 420 (M+H)⁺

Example 60 {4-[5-(3,5-Dimethyl-isoxazol-4-yl)-thiophen-2-yl]-7H-pyrrolo[2,3-<i]pyrimidin-2- yl } - [4-(2-pyrrolidin- 1 -yl-ethoxy)-phenyl] -amine

[0216] A suspension of 16 (90 mg, 0.21 mmol), nitoethane (80 μL, 1.12 mmol) and cesium carbonate (0.17 g, 0.52 mmol) in ethanol (4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 140 ⁰C for 40 min. After cooling to room temperature, the resulting mixture was filtered and the filtered solid washed with MeOH. The filtrate was concentrated and the residue purified by ΗPLC. The fractions were combined and poured into saturated NaHCO₃ solution (20 mL). The combined aqueous layers were extracted with EtOAc (2 x 20 mL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a light brown solid (15 mg, 14%).

[0217] ¹H NMR (500 MHz, DMSO-J₆): δ 1.65-1.73 (m, 4H), 2.41 (s, 3H), 2.50-2.60 (m, 4H), 2.61 (s, 3H), 2.75-2.85 (m, 2H), 4.05 (t, J = 5.9 Hz, 2H), 6.86 (dd, J = 3.6, 1.7 Hz, IH), 6.88 (d, J = 9.0 Hz, 2H), 7.28 (dd, J = 3.5, 2.3 Hz, IH), 7.36 (d, J = 3.9 Hz, IH), 7.77 (d, J = 9.1 Hz, 2H), 8.10 (d, J = 3.9 Hz, IH), 9.06 (s, IH), 11.62 (s, IH) MS (ES+): m/z 501 (M+H)⁺

Example 61 Preparation of intermediates:

25 l-Bromo-3-(2,2-dimethoxy-ethylsulfanyl)-benzene (25)

[0218] To a stirred solution of compound 3-bromo-benzenethiol (150 g, 0.80 mol) and compound 2-bromo-l,l-dimethoxy-ethane (135 g) in DMF (1500 mL) was added K2CO3 (165 g, 1.20 mol). The mixture was stirred overnight at room temperature (30 ⁰C). The mixture was filtered and the solvent of the filtrate was removed under reduced pressure. The residue was re-dissolved in EtOAc (2000 mL), washed with NaOH (IM, 500 mL), brine, dried over Na₂SO₄ and concentrated to give a crude product, which was purified by column chromatography (silica, elute; PE to PE:EtOAc=5:l) to afford the title compound (135 g, 70 %) as a light yellow oil.

26 6-Bromo-benzo[Z>]thiophene (26)

27 4-Bromo-benzo[Z>]thiophene (27)

[0219] Chlorobenzene (1000 niL) and PPA (280 g) were combined and heated to reflux (130 ⁰C). The solution of compound 25 (130 g, 0.48 mol) in chlorobenzene (300 mL) was added drop wise to the mixture over 1.5 h. The reaction mixture was refluxed for 3-4 h and then cooled. The solvent was decanted from the residue and toluene (400 mLx2 ) was added to the residue, stirred and decanted. The chlorobenzene/toluene extracts were combined and concentrated under vacuum, and the residue was then taken up with PE (800 mL) and water (400 mL). After layers separation the organic phase was washed with saturated NaHCO₃, brine, dried over Na₂SO₄ and concentrated to give a crude product, which was purified by column chromatography (silica gel, elute: PE) to afford a mixture of 26 and 27 (80 g, 70 %) as a colorless oil.

28

Benzo[Z>]thiophene-6-carbonitrile (28)

29

Benzo[b]thiophene-4-carbonitrile (29)

[0220] Under Ar atmosphere, to the mixture of compound 26 and compound 27 (40 g, 0.19 mol) and Zn(CN)₂ (16 g, 0.132 mol) were added Pd(PPh3)₄ (10 g) and DMF (800 mL) and the mixture was stirred at 90 ⁰C -100 ⁰C for 3 h. The reaction solution was cooled to room temperature (30 ⁰C) and filtered. The filtrate was concentrated under reduced pressure and the residue was then taken up with EtOAc (1000 mL) and saturated aq. NaHCO₃ (500 mL), the insoluble solid was discarded via filtration. The filtrate layers were separated. The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated to give a mixture product, which was purified by careful column chromatography (silica, elute; PE to EtO Ac:PE= 1:40) to afford compound 28 (14 g, 46.2 %) as an oil and compound 29 (7 g, 23%) as a solid.

30 ό-Cyano-benzothiophene^-boronic acid (30)

[0221] Compound 28 (14 g, 0.088 mol) in dry THF (350 mL) was purged with nitrogen. The mixture was then cooled (-90 ⁰C) with liquid nitrogen bath and ra-BuLi (2.5 M in hexanes, 42 mL, 0.105 mol) was added dropwise with stirred. The mixture was stirred for a further 30 min, and B(OMe)₃ (18 g, 0.173 mol) was added at -90 ⁰C. After 30 min, aqueous HCl (2M, 200 mL) was added. The mixture was stirred for a further 30 min, allowed to warm to room temperature (30 ⁰C), poured into water (100 mL). The mixture was extracted with EtOAc (400 mLx3). The combined organic layers were washed with water, brine, dried over Na₂SO₄ and concentrated to give a crude product, which was crystallized with EtOAc/PE (1:2, 100 mL) to give the title compound (12 g, 72%) as a white solid.

31

4-Cyano-benzothiophene-2-boronic acid (31)

[0222] Compound 29 (12 g, 0.076 mol) in dry THF (300 mL) was purged with nitrogen. The mixture was then cooled (-90 ⁰C) with liquid nitrogen bath and ra-BuLi (2.5 M in hexanes, 35 mL, 0.083 mol) was added dropwise with stirred. The mixture was stirred for a further 30 min, and B(OMe)₃ (16 g, 0.154 mol) was added at -90 ⁰C. After 30 min, aqueous HCl (2M, 200 mL) was added and solid was precipitated out. The mixture was stirred for a further 30 min, allowed to warm to room temperature (30 ⁰C), poured into water (100 mL). The mixture was extracted with EtOAc (300 mLx3). The combined organic layers were washed with water, brine, dried over Na₂SO₄ and concentrated to give a crude product, which was crystallized with EtOAc/PE (1:2, 100 rnL) to give the title compound (H g, 73%) as a white solid.

32 Benzo[Z>]thiophene-7-carbonitrile (32)

[0223] Under Ar atmosphere, to a mixture of 7-bromo-benzo[b]thiophene (40 g, 0.19 mol) and Zn(CN)₂ (16 g, 0.132 mol) were added Pd(PPh3)₄ (10 g) and DMF (800 mL) and the mixture was stirred at 90 ⁰C -100 ⁰C for 3 h. The reaction solution was cooled to room temperature (30 ⁰C) and filtered. The filtrate was concentrated under reduced pressure. The residue was taken up with EtOAc (1000 mL) and saturated aq. NaHCO₃ (500 mL) and then filtered. The filtrate layers were separated. The organic layer was washed with brine, dried over Na₂SO₄ and concentrated to give a crude product, which was purified by column chromatography (silica, elute; PE to EtOAc:PE=l:30) to afford the title compound (24 g, 80 %) as a white solid.

33 T-Cyano-benzothiophene^-boronic acid (33)

[0224] Compound 32 (20 g, 0.126 mol) in dry THF (500 mL) was purged with nitrogen. The mixture was then cooled (-90 ⁰C) with liquid nitrogen bath and ra-BuLi (2.5 M in hexanes, 60 mL, 0.15 mol) was added dropwise with stirred. The mixture was stirred for a further 30 min, and B(OMe)₃ (26 g, 0.25 mol) was added at -90 ⁰C. After 30 min, aqueous HCl (2M, 300 mL) was added and solid was precipitated out. The mixture was stirred for a further 30 min, allowed to warm to room temperature (30 ⁰C), poured into water (200 mL). The solid was filtered, washed with ice- water and dried to give the title compound (18 g, 72%) as a white solid. Example 62 Preparation of 2-{2-[4-(2-Pyrrolidin-l-yl-ethoxy)-phenylamino]-7H-pyrrolo[2,3- d]pyrimidin-4-yl}-benzo[b]thiophene-6-carbonitrile

[0225] To a microwave reaction tube was charged with 7 (0.10 g, 0.28 mmol), 30 (70 mg, 0.34 mmol) and Pd(PPh₃)₄ (30 mg, 0.026 mmol). DMF (3 mL) was added to the above mixture followed by 2 M of sodium carbonate (0.5 mL). The reaction tube was sealed and the suspension irradiated with microwave at 140 ⁰C for 20 min. After cooling to room temperature, the mixture was filtered, the filtered solid washed with DCM and the filtrate concentrated. The crude product was purified by ΗPLC, the fractions combined and poured into saturated NaHCO₃ solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a yellow solid (11 mg, 8%).

[0226] ¹H NMR (500 MHz, DMSO-J₆): δ 1.65-1.73 (m, 4H), 2.50-2.70 (m, 4H), 2.80-2.90 (m, 2H), 4.07 (t, J = 5.9 Hz, 2H), 6.92 (d, J = 9.1 Hz, 2H), 7.01 (dd, J= 3.7, 1.7 Hz, IH), 7.40 (dd, J = 3.6, 2.3 Hz, IH), 7.77 (d, J= 9.1 Hz, 2H), 7.81 (dd, J= 8.3, 1.4 Hz, IH), 8.16 (d, J = 8.3 Hz, IH), 8.59 (s, IH), 8.69 (d, / = 0.8 Hz, IH), 9.18 (s, IH), 11.75 (s, IH) MS (ES+): m/z 481 (M+H)⁺

Example 63 Preparation of intermediates

3,5-Dimethyl-4-thiophen-2-yl-isoxazole (34)

[0227] A mixture of thiophene-2-carbaldehyde (5.0 g, 45 mmol), nitoethane (7.0 niL, 98 mmol) and cesium carbonate (30 g, 92 mmol) in ethanol (45 mL) was heated at 110 ⁰C for 2 h. After cooling to room temperature, the resulting mixture was concentrated, taken up in water (40 mL) and extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the crude product purified by silica gel chromatography (hexanes to 10% EtOAc/hexanes) to afford the title compound as a pale brown solid (3.6 g, 45%).

¹K NMR (500 MHz, DMSO-J₆): δ 2.30 (s, 3H), 2.49 (s, 3H), 7.19 (dd, J = 5.0, 3.5 Hz, IH), 7.22 (dd, J = 3.5, 1.0 Hz, IH), 7.65 (dd, J = 5.1, 1.2 Hz, IH)

35 5-(3,5-dimethylisoxazol-4-yl)thiophen-2-yl-2-boronic acid (35)

[0228] To a solution of 34 (3.5 g, 19.6 mmol) in THF (30 mL) cooled at -78 ⁰C under argon atmosphere was added ra-BuLi (2.5 M in hexanes; 10 mL, 25 mmol). The mixture was stirred at the same temperature for 15 min and tri-isopropylborate added (8.5 mL, 37 mmol). The resulting mixture was stirred at at -78 ⁰C for 15 min and then stirred at RT for 2 h. The reaction was quenched with IM HCl (3 mL) and concentrated. The residue was taken up in water (40 mL) and extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the crude product purified by silica gel chromatography (hexanes to 50% EtOAc/hexanes) to afford the title compound as a grey solid (2.1 g, 37%).

[0229] ¹H NMR (500 MHz, DMSO-J₆): δ 2.32 (s, 3H), 2.51 (s, 3H), 7.24 (d, J = 3.5 Hz, IH), 7.70 (d, J = 3.5 Hz, IH), 8.29 (s, 2H)

36

(£')-/er/-Butyl(/er/-butoxycarbonylamino)(4-((2-methyl-lH-imidazol-l- yl)methyl)phenylamino)methylenecarbamate (36)

[0230] A slurry of N,Λ^-bis(fer?-butoxycarbonyl)-lH-pyrazole-l-carboxamidine (5.0 g, 16.1 mmol) and 4-(2-methylimidazol-l-ylmethyl)phenylamine (3.0 g, 16.1 mmol) in DMF (11 rnL) was stirred for 64 h. The resulting clear solution was poured into 100 rnL water and extracted with DCM (2x200 rnL) and ethyl acetate (1x100 rnL). The organic layers were combined and washed with brine (50 rnL), dried (Na₂SO₄), and concentrated in vacuo. The residual material was partially purified by silica gel column chromatography (0-20% MeOH in DCM with 0.05% ammonium hydroxide) to afford the title compound as a slightly impure yellow oil (6.6g, 95%)

[0231] ¹H NMR (500 MHz, DMSO-J₆) δ 1.45 (br s, 18H), 2.23 (s, 3H), 5.10 (s, 2H), 6.75 (d, J = 0.8 Hz, IH), 7.08-7.16 (m, 3H), 7.52 (d, J = 8.4 Hz, 2H), 9.98 (s, IH), 11.39 (s, IH) MS (ES+): m/z 430 (M+H)⁺

37 l-(4-((2-Methyl-lH-imidazol-l-yl)methyl)phenyl)guanidine (37)

[0232] To a solution of 36 (6.1 g, 14.2 mmol) in DCM (35 mL) was slowly added trifluoroacetic acid (35 mL) and the resulting mixture was stirred for 1.5 h at which point the reaction was concentrated in vacuo to afford the title compound contaminated with DMF and trifluroracetic acid as a yellow oil. It was used as is for the next reaction. MS (ES+): m/z 230 (M+H)⁺

38

2-[4-(2-Methyl-imidazol-l-ylmethyl)-phenylamino]-7H-pyrrolo[2,3-rf]pyrimidin-4- ol (38)

[0233] To a microwave reaction tube was charged with 37 (1.1 g, 5.0 mmol), 2-cyano-4,4- diethoxy-butyric acid ethyl ester (1.7 g, 7.4 mmol) and NaOMe (25% by wt in MeOH; 10 mL). The reaction tube was sealed and the solution irradiated with microwave at 150 ⁰C for 30 min. After cooling to room temperature, the mixture was concentrated. The residue was taken up in water (10 mL) and the pH adjusted to 1 with 6M of HCl. The resulting solution was stirred at room temperature for 25 min and then the pH adjusted to 9 with concentrated NH₄OH. The resulting solid was filtered, washed with water and dried under high vacuum to afford the title compound as a grey solid (1.5 g, 94%). The material was used in the next step without purification.

[0234] ¹H NMR (500 MHz, DMSO-J₆) δ 2.25 (s, 3H), 5.07 (s, 2H), 6.29 (dd, J = 3.0, 2.2 Hz, IH), 6.75 (t, J = 2.7 Hz, IH), 6.76 (d, J = 0.7 Hz, IH), 7.09-7.15 (m, 3H), 7.60 (d, J = 8.5 Hz, 2H), 8.71 (s, IH), 10.28 (br s, IH), 11.36 (s, IH) MS (ES+): m/z 321 (M+H)⁺

39

((4-Chloro-7H-pyrrolo[2,3-rf]pyrimidin-2-yl)-[4-(2-methyl-imidazol-l-ylmethyl)- phenyl] -amine (39)

[0235] A solution of 38 ( 1.4 g, 4.1 mmol) in POCl₃ (5 mL) was heated at 120 ⁰C for 30 min. After cooling to room temperature, the resulting dark solution was poured into ice water slowly and the pH adjusted to 9-10. The resulting solid was filtered, washed with water and dried under high vacuum to afford the title compound as a brown solid (1.1 g, 69%). The material was used in the next step without purification.

[0236] ¹H NMR (500 MHz, DMSO-J₆) δ 2.32 (s, 3H), 5.09 (s, 2H), 6.39 (dd, J = 3.3, 1.4 Hz, IH), 6.89 (d, J = 0.6 Hz, IH), 7.14 (d, J= 8.6 Hz, 2H), 7.19 (d, J= 0.8 Hz, IH), 7.27 (dd, J = 3.3, 2.1 Hz, IH), 7.77 (d, J= 8.6 Hz, 2H), 9.71 (s, IH), 11.93 (s, IH) MS (ES+): m/z 339 (M+H)⁺

Example 64 Preparation of {4-[5-(3,5-Dimethyl-isoxazol-4-yl)-thiophen-2-yl]-7H-pyrrolo[2,3- d]pyrimidin-2-yl } - [4-(2-methyl-imidazol- 1 -ylmethyl) -phenyl] -amine

[0237] To a microwave reaction tube was charged with 39 (0.10 g, 0.29 mmol), 35 (70 mg, 0.31 mmol) and Pd(PPh₃ )₄ (35 mg, 0.03 mmol). DMF (3 mL) was added to the above mixture followed by 2 M of sodium carbonate (0.5 mL). The reaction tube was sealed and the suspension irradiated with microwave at 140 ⁰C for 25 min. After cooling to room temperature, the mixture was filtered, the filtered solid washed with DCM and the filtrate concentrated. The crude product was purified by ΗPLC, the fractions combined and poured into saturated NaHCO₃ solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a yellow solid (30 mg, 21%).

[0238] ¹H NMR (500 MHz, DMSO-J₆): δ 2.27 (s, 3H), 2.41 (s, 3H), 2.60 (s, 3H), 5.05 (s, 2H), 6.76 (d, J = 1.0 Hz, IH), 6.89 (dd, J = 3.6, 1.7 Hz, IH), 7.09-7.14 (m, 3H), 7.32 (dd, J = 3.6, 2.3 Hz, IH), 7.37 (d, J= 3.9 Hz, IH), 7.87 (d, J= 8.6 Hz, 2H), 8.11 (d, J= 3.9 Hz, IH), 9.31 (s, IH), 11.68 (s, IH) MS (ES+): m/z 482 (M+H)⁺ Example 65 Preparation of 2-{2-[4-(2-Methyl-imidazol-l-ylmethyl)-phenylamino]-7H- pyrrolo[2,3-d]pyrimidin-4-yl}-benzo[b]thiophene-6-carbonitrile

[0239] To a microwave reaction tube was charged with 39 (0.10 g, 0.29 mmol), 30 (80 mg, 0.39 mmol) and Pd(PPh₃)₄ (30 mg, 0.026 mmol). DMF (4 mL) was added to the above mixture followed by 2 M of sodium carbonate (0.5 mL). The reaction tube was sealed and the suspension irradiated with microwave at 150 ⁰C for 20 min. After cooling to room temperature, the mixture was filtered, the filtered solid washed with DCM and the filtrate concentrated. The crude product was purified by ΗPLC, the fractions combined and poured into saturated NaHCO₃ solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a yellow solid (10 mg, 7%).

[0240] ¹H NMR (500 MHz, DMSO-J₆): δ 2.28 (s, 3H), 5.08 (s, 2H), 6.78 (d, J = 0.9 Hz, IH), 7.05 (dd, J = 3.6, 1.7 Hz, IH), 7.13-7.17 (m, 3H), 7.45 (dd, J = 3.5, 2.4 Hz, IH), 7.81 (dd, J = 8.2, 1.4 Hz, IH), 7.89 (d, J= 8.6 Hz, 2H), 8.16 (d, J= 8.3 Hz, IH), 8.62 (s, IH), 8.71 (d, J = 0.8 Hz, IH), 9.44 (s, IH), 11.83 (s, IH) MS (ES+): m/z 462 (M+H)⁺

Example 66 Preparation of {4-[5-(3-Isopropoxy-phenyl)-thiophen-2-yl]-7H-pyrrolo[2,3- d]pyrimidin-2-yl } - [4-(2-pyrrolidin- 1 -yl-ethoxy)-phenyl] -amine

[0241] To a microwave reaction tube was charged with 4-(5-Chloro-thiophen-2-yl)-7H- pyrrolo[2,3-(i]pyrimidin-2-yl]-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-amine (25 mg, 0.057 mmol), 3-isoproxybenzene boronic acid (15 mg, 0.083 mmol) and Pd(PPlIs)₄ (10 mg, 0.087 mmol). DMF (3 mL) was added to the above mixture followed by 2 M of sodium carbonate (0.2 mL). The reaction tube was sealed and the suspension irradiated with microwave at 150 ⁰C for 20 min. After cooling to room temperature, the mixture was filtered, the filtered solid washed with DCM and the filtrate concentrated. The crude product was purified by ΗPLC, the fractions combined and poured into saturated NaHCO₃ solution (20 mL). The combined aqueous layers were extracted with EtOAc (2 x 20 mL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a yellow solid (17 mg, 55%). ¹H NMR (500 MHz, DMSO-J₆): δ 1.32 (d, J = 6.0 Hz, 6H), 1.68-1.78 (m, 4H), 2.50-2.80 (m, 4H), 2.80-2.95 (m, 2H), 4.03-4.10 (m, 2H), 4.74 (qn, J = 6.0 Hz, IH), 6.80-6.95 (m, 4H), 7.26-7.32 (m, 3H), 7.37 (t, J = 8.0 Hz, IH), 7.68 (d, J = 3.9 Hz, IH), 7.79 (d, J = 9.1 Hz, 2H), 8.06 (d, J = 4.0 Hz, IH), 9.05 (s, IH), 11.60 (s, IH) MS (ES+): m/z 540 (M+H)⁺

Example 67 Preparation of Intermediate

40 [4-(5-Chloro-thiophen-2-yl)-7H-pyrrolo[2,3-rf]pyrimidin-2-yl]-[4-(2-methyl- imidazol-l-ylmethyl)-phenyl]-amine (40)

[0242] To a microwave reaction tube was charged with 39 (0.30 g, 0.88 mmol), 5- chlorothiophene-2-boronic acid (0.19 g, 1.2 mmol) and Pd(PPh₃)₄ (0.10 g, 0.087 mmol). DMF (4 mL) was added to the above mixture followed by 2 M of sodium carbonate (1.0 mL). The reaction tube was sealed and the suspension irradiated with microwave at 150 ⁰C for 20 min. After cooling to room temperature, the mixture was filtered, the filtered solid washed with DCM and the filtrate concentrated. The crude product was purified by silica gel chromatography (DCM to 15% MeOH/DCM) to afford the title compound as a brown oil (0.17 g, 46%).

MS (ES+): m/z 421 (M+H)⁺

Example 68 N-fert-Butyl-3-(5-{2-[4-(2-methyl-imidazol-l-ylmethyl)-phenylamino]-7H- pyrrolo[2,3-d]pyrimidin-4-yl}-thiophen-2-yl)-benzenesulfonamide

[0243] To a microwave reaction tube was charged with 40 (80 mg, 0.19 mmol), 4-(N-tert- butylsulfamoyl)-2-benzene boronic acid (70 mg, 0.27 mmol) and Pd(PPh₃)₄ (20 mg, 0.017 mmol). DMF (4 mL) was added to the above mixture followed by 2 M of sodium carbonate (0.5 mL). The reaction tube was sealed and the suspension irradiated with microwave at 150 ⁰C for 20 min. After cooling to room temperature, the mixture was filtered, the filtered solid washed with DCM and the filtrate concentrated. The crude product was purified by HPLC, the fractions combined and poured into saturated NaHCO₃ solution (20 mL). The combined aqueous layers were extracted with EtOAc (2 x 20 mL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the residue triturated in a mixture of EtOAc/hexanes (1/5). After filtration, the title compound was obtained as a yellow solid (50 mg, 44%).

[0244] ¹H NMR (500 MHz, DMSO-J₆): δ 1.14 (s, 9H), 2.27 (s, 3H), 5.05 (s, 2H), 6.75 (d, J = 0.9 Hz, IH), 6.92 (dd, J = 3.6, 1.7 Hz, IH), 7.11 (d, J = 1.0 Hz, IH), 7.13 (d, J= 8.6 Hz, IH), 7.34 (dd, J = 3.4, 2.4 Hz, IH), 7.68 (t, J= 7.8 Hz, IH), 7.71 (s, IH), 7.77 (d, J= 4.0 Hz, IH), 7.81 (d, J = 8.0 Hz, IH), 7.88 (d, J = 8.6 Hz, 2H), 8.03 (d, J = 7.9 Hz, IH), 8.14 (d, J = 4.0 Hz, IH), 8.18 (t, J = 1.7 Hz, IH), 9.33 (s, IH), 11.71 (s, IH) MS

(ES+): m/z 598 (M+H)⁺

Example 69 Preparation of Intermediates

41 6-Thiophen-2-yl-2,3-dihydro-benzo[l,4]dioxine (41)

[0245] To a reaction flask was charged with thiophene-2-carbaldehyde (2.3 g, 14 mmol), 5- (2,3-dihydrobenzo[b][l,4]dioxin-7-yl)thiophen-2-yl-2-boronic acid (3.0 g, 17 mmol) and Pd(PPh₃ )₄ (1.0 g, 0.87 mmol). DMF (20 mL) was added to the above mixture followed by 2 M of sodium carbonate (15 mL). The reaction was heated at 120 ⁰C for 2 h. After cooling to room temperature, the mixture was filtered and the filtrate diluted with water. The combined mixture was extracted with EtOAc (2 x 40 mL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the crude product was purified by silica gel chromatography (10% EtOAc/hexanes) to afford the title compound as a colorless oil (2.9 g, 94%).

42 5-(2,3-Dihydro-benzo[l,4]dioxin-6-yl)-thiophene-2-boronic add (42)

[0246] To a solution of 41 (2.9 g, 13 mmol) in THF (20 niL) cooled at -78 ⁰C under argon atmosphere was added ra-BuLi (2.5 M in hexanes; 8.0 rnL, 20 mmol). The mixture was stirred at the same temperature for 15 min and tri-isopropylborate added (5.0 mL, 22 mmol). The resulting mixture was stirred at at -78 ⁰C for 5 min and then stirred at RT for 2 h. The reaction was quenched with IM HCl until pH~l and the mixture stirred for 5 min. The mixture was extracted with EtOAc (2 x 40 mL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the residue triturated in a mixture of EtOAc/hexanes (1/10). After filtration, the title compound was obtained as a lime solid (2.8 g, 80%).

[0247] ¹H NMR (500 MHz, DMSO-J₆): δ 4.26 (s, 4H), 6.89 (d, J = 8.3 Hz, IH), 7.10-7.17 (m, 2H), 7.38 (d, J = 3.5 Hz, IH), 7.60 (d, J= 3.5 Hz, IH), 8.20 (s, 2H)

Example 70 Preparation of {4-[5-(2,3-Dihydro-benzo[l,4]dioxin-6-yl)-thiophen-2-yl]-7H- pyrrolo[2,3-d]pyrimidin-2-yl } - [4-(2-methyl-imidazol- 1 -ylmethyl)-phenyl] -amine

[0248] To a microwave reaction tube was charged with 40 (0.10 g, 0.30 mmol), 42 (0.10 g, 0.38 mmol) and Pd(PPh₃)₄ (30 mg, 0.026 mmol). DMF (3 mL) was added to the above mixture followed by 2 M of sodium carbonate (0.5 mL). The reaction tube was sealed and the suspension irradiated with microwave at 150 ⁰C for 20 min. After cooling to room temperature, the mixture was filtered, the filtered solid washed with DCM and the filtrate concentrated. The crude product was purified by HPLC, the fractions combined and poured into saturated NaHCO₃ solution (20 mL). The combined aqueous layers were extracted with EtOAc (2 x 20 mL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a yellow solid (80 mg, 52%).

[0249] ¹H NMR (500 MHz, DMSO-J₆): δ 2.28 (s, 3H), 4.30 (s, 4H), 5.06 (s, 2H), 6.75 (d, J = 1.1 Hz, IH), 6.88 (dd, J = 3.6, 1.8 Hz, IH), 6.96 (d, J = 8.3 Hz, IH), 7.10-7.15 (m, 3H), 7.24 (dd, J = 8.3, 2.3 Hz, IH), 7.27 (d, J = 2.2 Hz, IH), 7.30 (dd, J = 3.5, 2.4 Hz, IH), 7.54 (d, J = 3.9 Hz, IH), 7.88 (d, J = 8.7 Hz, 2H), 8.03 (d, J = 4.0 Hz, IH), 9.27 (s, IH), 11.64 (s, IH)

MS (ES+): m/z 521 (M+H)⁺

Example 71 {4-[5-(3-Isopropoxy-phenyl)-thiophen-2-yl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl}- [4-(2-methyl-imidazol- 1 -ylmethyl)-phenyl] -amine

[0250] To a microwave reaction tube was charged with 40 (80 mg, 0.19 mmol), 3- isoproxybenzene boronic acid (50 mg, 0.28 mmol) and Pd(PPh₃)₄ (20 mg, 0.017 mmol). DMF (4 mL) was added to the above mixture followed by 2 M of sodium carbonate (0.5 mL). The reaction tube was sealed and the suspension irradiated with microwave at 150 ⁰C for 20 min. After cooling to room temperature, the mixture was filtered, the filtered solid washed with DCM and the filtrate concentrated. The crude product was purified by HPLC, the fractions combined and poured into saturated NaHCO₃ solution (20 rnL). The combined aqueous layers were extracted with EtOAc (2 x 20 rnL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the residue re- dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a yellow solid (30 mg, 30%).

[0251] ¹H NMR (500 MHz, DMSO-J₆): δ 1.32 (d, J = 6.0 Hz, 6H), 2.28 (s, 3H), 4.74 (qn, J = 6.0 Hz, IH), 5.06 (s, 2H), 6.75 (s, IH), 6.90 (d, J = 1.7 Hz, IH), 6.95 (d, J = 6.6 Hz, IH), 7.10-7.15 (m, 3H), 7.26-7.33 (m, 3H), 7.38 (t, J = 7.9 Hz, IH), 7.68 (d, J = 3.8 Hz, IH), 7.88 (d, J = 8.5 Hz, 2H), 8.07 (d, J = 3.9 Hz, IH), 9.28 (s, IH), 11.66 (s, IH)

MS (ES+): m/z 521 (M+H)⁺

Example 72 Preparation of Intermediates

43

(£)-/er/-Butyl(/er/-butoxycarbonylamino)(3-(4-methyl-piperazin-l-yl)- phenylamino)methylenecarbamate (43)

[0252] To a solution of N,Λ^-bis(fer?-butoxycarbonyl)-lH-pyrazole-l-carboxamidine (264 g, 0.85 mol) in CH₃CN (2500 mL) was added 3-(4-methyl-piperazin-l-yl)-phenylamine (195 g, 1.02 mol), and the mixture was stirred at 25 ⁰C for 20 h. Upon completion, the precipitate was collected by filtration and washed with CH₃CN (400 mL) to afford the title compound (336 g, 91%) as an off-white solid.

44 N-[3-(4-Methyl-piperazin-l-yl)-phenyl]-guanidine (44)

[0253] To a solution of 43 (336 g, 0.77 mol) in DCM (3 L) was added dropwise TFA (1.5 L) at 10-15 ⁰C. After the addition completed, the mixture was stirred for 12 h at 25 ⁰C. Upon completion, the reaction mixture was condensed and the residue was poured into ice water. The resulting mixture was basified with 40% NaOH aqueous solution until no more solid separated from the mixture. The solution was extracted with CHCI₃/THF (3/1, 16 L) and washed with brine, dried over Na₂SO₄, and condensed to afford the title compound (173 g, 96%) as an off-white solid.

45

6-Amino-5-(2,2-diethoxy-ethyl)-2-[3-(4-methyl-piperazin-l-yl)-phenylamino]- pyrimidin-4-ol (45)

[0254] Compound 44 (2.5 g, 10.7 mmol) and 2-cyano-4,4-diethoxy-butyric acid ethyl ester (3.2 g, 13.0 mol) were suspended in 15 mL of sodium ethoxide solution (2.8 g of sodium dissolved in 60 mL of ethanol), and the reaction mixture irradiated with microwave at 140 ⁰C for 30 min. TLC (DCM: MeOH = 10:1) showed the starting material was reacted completely. The reaction mixture was cooled and evaporated under reduced pressure to get the residue, which was dissolved in a mixture of water (20 mL) and EtOAc (20 mL). The aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated to afford the title compound (4.0 g, 90%) as a white solid.

46 2-[3-(4-Methyl-piperazin-l-yl)-phenylamino]-7H-pyrrolo[2,3-rf]pyrimidin-4-ol

(46)

[0255] Compound 45 (140 g, 0.168 mol) was dissolved in hydrogen chloride solution (1 M, 1400 niL), and the solution stirred at 17-23 ⁰C for 2 h. TLC (DCM: MeOH = 10:1) showed the starting material was converted completely. The reaction mixture was neutralized with aqueous potassium carbonate solution to pH 8, and large amount of precipitate was formed. The resulting precipitate was collected by filtration, washed with water to afford the title compound (90 g, 83%) as an off-white solid.

47

(4-Chloro-7H-pyrrolo[2,3-rf]pyrimidin-2-yl)-[3-(4-methyl-piperazin-l-yl)-phenyl]- amine (47)

[0256] To a stirred POCl₃ (0.8 L) was added compound 46 (80 g, 0.24 mol) in portions and the reaction mixture heated to 100 ⁰C for 2 h. TLC (DCM: MeOH = 10:1) showed the starting material was converted completely. The reaction mixture was cooled and evaporated under reduced pressure to remove the excess POCl₃. Water was added to the residue carefully, and heat was generated during the addition of water. The aqueous layer was extracted with EtOAc (1 Lx 3). The combined organics layer were washed with water and brine, dried over sodium sulfate, and concentrated to get the residue, which was purified by column chromatography (DCM: MeOH = 50:1 to 20: 1) to afford the title compound (56 g, 67%) as an off-white solid.

48 Benzo[Z>]thiophen-5-yl-morpholin-4-yl-methanone (48)

[0257] To a solution of benzo[b]thiophene-5-carbonyl chloride (0.55 g, 2.8 mmol) in DCM (15 niL) was added morpholine (1 niL, 11 mmol). The mixture was stirred at 60 ⁰C for 2 h and then poured into water (20 mL). The mixture was extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the crude product (0.65 g, 94%) as a colorless gel used in the next step without purification.

49 5-(Morpholinocarbonyl)benzo[b]thiophen-2-boronic acid (49)

[0258] To a solution of 48 (0.65 g, 2.6 mmol) in THF (8 mL) cooled at -78 ⁰C under argon atmosphere was added £-BuLi (1.7 M in pentanes; 2.0 mL, 3.4 mmol). The mixture was stirred at the same temperature for 15 min and tri-isopropylborate added (0.8 mL, 3.5 mmol). The resulting mixture was stirred at at -78 ⁰C for 1.5 h and then quenched with IM HCl until pH~l at room temperature. The mixture was stirred for additional 30 min and then extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the crude product (0.45 g, 59%) was used in the next step without purification. Example 73 Preparation of (2-{2-[3-(4-Methyl-piperazin-l-yl)-phenylamino]-7H-pyrrolo[2,3- d]pyrimidin-4-yl}-benzo[b]thiophen-5-yl)-moφholin-4-yl-methanone

[0259] To a microwave reaction tube was charged with 49 (0.15 g, 0.52 mmol), 47 (0.10 g, 0.29 mmol) and Pd(PPh₃ )₄ (30 mg, 0.026 mmol). DMF (4 mL) was added to the above mixture followed by 2 M of sodium carbonate (0.5 mL). The reaction tube was sealed and the suspension irradiated with microwave at 150 ⁰C for 20 min. After cooling to room temperature, the mixture was filtered, the filtered solid washed with DCM and the filtrate concentrated. The crude product was purified by HPLC, the fractions combined and poured into saturated NaHCO₃ solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a yellow solid (10 mg, 4%).

[0260] ¹H NMR (500 MHz, DMSO-J₆): δ 2.28 (s, 3H), 2.40-2.60 (m, 4H), 3.10-3.23 (m, 4H), 3.50-3.75 (m, 8H), 6.52 (dd, J = 8.2, 2.1 Hz, IH), 7.00 (dd, J = 3.6, 1.7 Hz, IH), 7.13 (t, J = 8.1 Hz, IH), 7.34 (dd, J = 8.0, 1.4 Hz, IH), 7.42 (dd, J= 3.5, 2.4 Hz, IH), 7.49 (dd, J = 8.3, 1.5 Hz, IH), 7.66 (t, J = 1.9 Hz, IH), 8.06 (d, J = 1.1 Hz, IH), 8.11 (d, J = 8.4 Hz, IH), 8.54 (s, IH), 9.15 (s, IH), 11.74 (s, IH)

MS (ES+): m/z 554 (M+H)⁺

Example 74 Preparation of Intermediates

50 4-Methyl-l-(3-nitro-5-trifluoromethyl-phenyl)-lH-imidazole (50)

[0261] Tetramethylammonium fluoride (200 g, 2.15 mol) was added to a solution of 1,3- dinitro-5-trifluoromethyl-benzene (200 g, 0.847 mol) in DMSO (2 L). The mixture was heated to 100-110 ⁰C for 4 h. TLC (Petroleum ether: EtOAc=20:l) showed -50% of starting material has been converted into mono fluoro substituted intermediate. 4-Methyl- IH- imidazole (200 g, 2.43 mol) was added to the reaction mixture, and the resulting solution was heated to 140 ⁰C overnight. TLC (Petroleum ether: EtOAc=20:l) showed the aforementioned intermediate disappeared. The reaction mixture was cooled to room temperature, and then added with water (10 L). The resulting mixture was extracted with DCM (2 L x 2). The combined organic layers were concentrated to give a crude product, which was purified by chromatography (silica, elute; Petroleum ether: EtOAc = 5:1→3:1) to give the title compound (34 g, 15%) as a yellow solid.

51 3-(4-Methyl-imidazol-l-yl)-5-trifluoromethyl-phenylamine (51)

[0262] Fe powder (20 g, 0.36 mol) and NH₄Cl (20 g, 0.38 mol) were added to a solution of compound 50 (20 g, 0.07 mol) in a mixture of EtOH (400 mL) and water (100 mL). The mixture was refluxed for 3 h under nitorgen. TLC (DCM: MeOH = 10:1) showed compound 50 disappeared. The reaction mixture was filtered and the filter cake washed with THF (100 mL x 2). The filtrate was dried over Na₂SO₄, and concentrated to give the title compound (12 g, 68%) as an off-white solid. Example 75 [3-(4-Methyl-imidazol- l-yl)-5-trifluoromethyl-phenyl]-[4-(4-methyl-thiophen-2- yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-amine

[0263] A suspension of 1 (0.10 g, 0.40 mmol), 51 (0.13 g, 0.54 mmol), Pd₂(dba)₃ (25 mg, 0.027 mmol), tή-tert-buty\ phosphine (IM in toluene; 0.1 mL, 0.10 mmol) and potassium tert- butoxide (0.25 g, 2.2 mmol) in dioxane/DMF (1/1; 6 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 ⁰C for 30 min. After cooling to room temperature, the resulting mixture was filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO₃ solution (20 mL). The combined aqueous layers were extracted with

EtOAc (2 x 20 mL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a light brown solid (23 mg, 13%).

[0264] ¹K NMR (500 MHz, DMSO-J₆): δ 2.20 (s, 3H), 2.33 (s, 3H), 6.93 (dd, J = 3.6, 1.7 Hz, IH), 7.41 (dd, J = 3.6, 2.3 Hz, IH), 7.44 (s, 2H), 7.50 (s, IH), 7.97 (s, IH), 8.20 (d, J = 0.8 Hz, IH), 8.27 (s, IH), 8.46 (s, IH), 11.84 (s, IH)

MS (ES+): m/z 455 (M+H)⁺

Example 76 4-(4-Methylthiophen-2-yl)-N-(4-(l-moφholinoethyl)phenyl)-7H-pyrrolo[2,3- d]pyrimidin-2- amine hydrochloride

[0265] In a microwave vial was sequentially added 9 (0.30 g, 0.74 mmol), Pd(OAc)₂ (0.017 g, 0.074 mmol), DMF (5 mL), 4-(-l-morpholinoethyl)aniline (0.18 g, 0.89 mmol), P(J-Bu)₃ (1 M in toluene, 0.15 mL, 0.15 mmol), and triethylamine (1.0 mL, 7.4 mmol). The reaction mixture was heated at 180 ⁰C for 20 min in a Biotage microwave reactor. The resulting mixture was separated by preparative HPLC. Fractions that contained the desired product were combined, neutralized with saturated Na₂CO₃, and extracted with EtOAc. The organic layer was dried over MgSO₄ and concentrated to afford the tysolated intermediate as brown oil. The brown oil was re-dissolved in methanol (20 mL) and cesium carbonate (2.4 g, 7.4 mmol) was added. The reaction mixture was stirred at 60 ⁰C for 30 min then cooled to room temperature. The resulting mixture was concentrated and re-dissolved in EtOAc (20 mL). The solution was extracted with saturated Na₂CO₃ (10 mL), washed with water (10 mL), washed with brine (10 mL), and dried over MgSO₄. A solution of 4 M HCl in 1,4-dioxane (0.2 mL) was added and the mixture was evaporated to afford the title compound as a brown solid (0.032 g).

[0266] ¹H NMR (500 MHz, DMSO-J₆): δ 1.70 (d, J = 6.9 Hz, 3H), 2.81-2.85 (m, 2H), 2.89-2.98 (m, 2H), 3.60-3.62 (m, 2H), 3.93-3.96 (m, 2H), 4.38 (quin, J = 6.6 Hz, IH), 6.88 (dd, J = 3.5, 1.6 Hz, IH), 7.34 (dd, J= 3.3, 2.6 Hz, IH), 7.42 (s, IH), 7.52 (d, J= 8.7 Hz, 2H), 7.95 (s, IH), 8.00 (d, J = 8.7 Hz, 2H), 9.51 (s, IH), 11.16 (s, IH), 11.75 (s, IH)

MS (ES+): m/z 420 (M+H)⁺

Example 77 N-(4-(2-Methyl-lH-imidazol-l-yl)phenyl)-4-(4-methylthiophen-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine hydrochloride

[0267] In a microwave vial was sequentially added 9 (0.20 g, 0.50 mmol), Pd(OAc)₂ (0.011 g, 0.050 mmol), DMF (3 mL), 4-(2-methyl-lH-imidazol-l-yl)aniline (0.10 g, 0.59 mmol), P(f- Bu)₃ (1 M in toluene, 0.1 mL, 0.1 mmol), and triethylamine (0.7 mL, 5.0 mmol). The reaction mixture was heated at 180 ⁰C for 20 min in a Biotage microwave reactor. The resulting mixture was separated by preparative ΗPLC. Fractions that contained the desired product were combined, neutralized with saturated Na₂CO₃, and extracted with EtOAc. The organic layer was dried over MgSO₄ and concentrated to afford the tysolated intermediate as brown oil. The brown oil was re-dissolved in methanol (20 mL) and cesium carbonate (1.1 g, 3.4 mmol) was added. The reaction mixture was stirred at 60 ⁰C for 30 min then cooled to room temperature. The resulting mixture was concentrated and re-dissolved in EtOAc (20 mL). The solution was extracted with saturated Na₂CO₃ (20 mL), washed with water (20 mL), washed with brine (10 mL), and dried over MgSO₄. A solution of 4 M HCl in 1,4-dioxane (0.2 mL) was added and the mixture was evaporated to afford the title compound as a brown solid (0.022 g).

[0268] ¹H NMR (500 MHz, DMSO-J₆): δ 2.33 (s, 3H), 2.55 (s, 3H), 6.90-6.92 (m, IH), 7.37 (dd, J = 5.8, 2.5 Hz, IH), 7.42 (s, IH), 7.52 (d, J = 8.9 Hz, 2H), 7.76 (d, J = 1.9 Hz, IH), 7.86 (d, J = 2.0 Hz, IH), 7.96 (s, IH), 8.14 (d, J = 8.9 Hz, 2H), 9.71 (s, IH), 11.78 (s, IH), 11.72 (s, IH)

MS (ES+): m/z 387 (M+H)⁺

Example 78 2-(4-(4-(4-Methylthiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamido)acetic acid

[0269] In a microwave vial was sequentially added 9 (0.20 g, 0.50 mmol), Pd(OAc)₂ (0.011 g, 0.050 mmol), DMF (3 mL), 4-aminohippuric acid (0.12 g, 0.59 mmol), P(J-Bu)₃ (1 M in toluene, 0.1 mL, 0.1 mmol), and triethylamine (0.7 mL, 5.0 mmol). The reaction mixture was heated at 180 ⁰C for 20 min in a Biotage microwave reactor. The resulting mixture was separated by preparative HPLC. Fractions that contained the desired product were combined, neutralized with saturated Na₂CO₃, and extracted with EtOAc. The organic layer was dried over MgSO₄ and concentrated to afford the tysolated intermediate as brown oil. The brown oil was re-dissolved in methanol (20 mL) and cesium carbonate (1.1 g, 3.4 mmol) was added. The reaction mixture was stirred at 60 ⁰C for 30 min then cooled to room temperature. The resulting mixture was concentrated and re-dissolved in EtOAc (20 mL). The solution was extracted with saturated Na₂CO₃ (20 mL), washed with water (20 mL), washed with brine (10 mL), and dried over MgSO₄ to afford the title compound as a brown solid (0.0185 g, 9%).

[0270] ¹H NMR (500 MHz, DMSO-J₆): δ 2.33 (s, 3H), 3.65 (s, 2H), 6.90 (dd, J = 3.4, 1.4 Hz, IH), 7.36 (dd, J = 5.6, 2.5 Hz, IH), 7.42 (s, IH), 7.82 (d, J = 8.8 Hz, 2H), 7.95 (s, IH), 8.00 (d, J = 8.8 Hz, 2H), 9.63 (s, IH), 10.81 (s, IH), 11.77 (s, IH), 11.95 (s, IH)

MS (ES+): m/z 408 (M+H)⁺

Example 79 Preparation of 4-(4-Methylthiophen-2-yl)-N-(4-(pyrrolidin-l-ylmethyl)phenyl)- 7H-pyrrolo[2,3-d]pyrimidin-2-amine

[0271] In a microwave vial was charged 9 (0.30 g, 0.74 mmol), Pd)₂(dba)₃ (0.034 g, 0.037 mmol), 4-(pyrrolidin-l-ylmethyl)aniline (0.23 g, 0.89 mmol), Xantphos (0.043 g, 0.075 mmol), and cesium carbonate (1.21 g, 3.7 mmol) in 1,4-dioxane and (3.6 mL) and DMF (0.4 mL). The reaction mixture was heated at 160 ⁰C for 30 min in a Biotage microwave reactor. The resulting mixture was concentrated and re-dissolved in methanol (10 mL) followed by addition of cesium carbonate (1.0 g, 3.1 mmol). The mixture was heated at 60 oC for 30 min and filtered through a pad of silica gel. The crude mixture was separated by preparative HPLC. Fractions that contained the desired product were combined, neutralized with saturated Na₂CO₃, and extracted with EtOAc. The organic layer was dried over MgSO₄ to afford the title compound as a yellow solid (0.034 g, 12%).

[0272] ¹H NMR (500 MHz, DMSO-J₆): δ 1.74 (s, 4H), 2.32 (s, 3H), 2.58-2.66 (br s, 2H), 3.63-3.72 (br s, 2H), 6.85 (dd, J = 3.6, 1.6 Hz, IH), 7.24 (d, J = 7.6 Hz, 2H), 7.29 (dd, J= 3.4, 2.5 Hz, IH), 7.39 (d, J = 0.9 Hz, IH), 9.22 (s, IH), 11.62 (s, IH)

MS (ES+): m/z 390 (M+H)⁺

Example 80 Preparation of Intermediate

52 5-(2-Chloro-7H-pyrrolo[2,3-rf]pyrimidin-4-yl)thiophene-2-carboxamide (52)

[0273] Compound 12 (100 mg, 0.23 mmol) was treated with tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 5 mL, 5 mmol). The mixture was heated under reflux for 20 min. The solvent was removed in vacuo and the residue was dissolved in EtOAc (50 mL). The solution was washed with saturated NaHCO₃ (2 x 50 mL). The crude product (30 mg, 47%) was used for next step without further purification.

Example 81 Preparation of 5-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)thiophene-2-carboxamide

[0274] To a solution of 52 (30 mg, 0.11 mmol) in 1,4-dioxane (10 niL) and DMF (5 niL) was added 4-(4-methylpiperazin-l-yl)benzenamine (21 mg, 0.11 mmol), KO^-Bu (45 mg, 0.4 mmol), Pd₂(dba)₃ (9 mg, 0.01 mmol), and 1.0 M tri-te/t-butylphosphine in toluene (0.03 mL, 0.03 mmol). The reaction mixture was heated at 150 ⁰C for 20 min under μ-wave. The solid was filtered off and the filtrate washed with brine (1 x 50 mL). The organic solution was separated and dried (Na₂SO₄). The solvent was removed in vacuo. The crude product was purified by HPLC. The HPLC fractions containing product were combined and neutralized with saturated NaHCO₃ (50 mL). The free base was extracted with EtOAc (2 x 50 mL). The organic layers were combined and dried (Na₂SO₄). The solvent was removed in vacuo. The residue was dissolved in MeOH (2 mL) and 4.0 M HCl solution (0.1 mL, 0.4 mmol) in dioxane was added. The solution was stirred for 5 min at room temperature and then concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and anhydrous Et₂O (20 mL) was added. The solid was collected by centrifuging. The title compound (5 mg, 10%) was afforded as a orange solid.

[0275] ¹H NMR (500 MHz, DMSO-J₆): δ 2.83 (d, J = 4.6 Hz, 3H), 2.97-3.02 (m, 2H), 3.14-3.21 (m, 2H), 3.49-3.52 (m, 2H), 3.73 (d, J = 13.3 Hz, 2H), 6.86-6.87 (m, IH), 6.98 (d, J = 9.1 Hz, 2H), 7.31-7.32 (m, IH), 7.54 (br s, IH), 7.76 (d, J = 9.1 Hz, 2H), 7.86 (d, J= 4.0 Hz, IH), 8.06 (d, J = 4.0 Hz, IH), 8.14 (br s, IH), 9.11 (s, IH), 10.29 (br s, IH), 11.64 (s, IH)

MS (ES+): m/z 434 (M+H)⁺

Example 82 Preparation of 2-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)benzo[b]thiophene-7-carbonitrile

[0276] To a solution of 20 (86 mg, 0.25 mmol) in dimethoxyethane (DME, 10 niL) was added a solution of 33 (61 mg, 0.3 mmol) in EtOH (5 mL), 2.0 M Na₂CO₃ (0.5 mL), and tetrakis(triphenylphosphine)palladium (0) (Pd(PPh₃ )₄, 28 mg, 0.025 mmol). The reaction mixture was heated at 110 ⁰C for 20 min under μ-wave. The hot solution was filtered and the solid washed with EtOAc. The organic solution was separated and the aqueous layer extracted with EtOAc (2 x 50 mL). The combined organic layers were dried (Na₂SO₄). The solvent was removed in vacuo. The crude product was purified by HPLC. The HPLC fractions containing product were combined and neutralized with saturated NaHCO₃ (50 mL). The free base was extracted with EtOAc (2 x 100 mL). The organic layers were combined and dried (Na₂SO₄). The solvent was removed in vacuo. The residue was dissolved in MeOH (2 mL) and 4.0 M HCl solution (0.3 mL, 1.2 mmol) in dioxane was added. The solution was stirred for 5 min at room temperature and then concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and anhydrous Et₂O (20 mL) was added. The solid was collected by centrifuging. The title compound (30 mg, 24%) was afforded as a yellow solid.

[0277] ¹H NMR (500 MHz, DMSO-J₆): δ 2.82 (d, J = 4.5 Hz, 3H), 3.06 (t, J = 11.9 Hz, 2H), 3.16-3.22 (m, 2H), 3.49 (d, J = 11.3 Hz, 2H), 3.73 (d, J = 13.2 Hz, 2H), 6.98 (d, J = 9.1 Hz, 2H), 7.03-7.04 (m, IH), 7.40-7.41 (m, IH), 7.65 (t, J = 1.9 Hz, IH), 7.79 (d, / = 9.1 Hz, 2H), 8.03 (d, J = 7.4 Hz, IH), 8.33 (d, J = 7.4 Hz, IH), 8.65 (s, IH), 9.23 (br s, IH), 10.72 (br s, IH), 11.79 (s, IH)

MS (ES+): m/z 466 (M+H)⁺

Example 83 Preparation of 2-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)benzo[b]thiophene-4-carbonitrile

[0278] To a solution of 20 (70 mg, 0.20 mmol) in dimethoxyethane (DME, 10 niL) was added a solution of 31 (50 mg, 0.25 mmol) in EtOH (5 mL), 2.0 M Na₂CO₃ (0.5 mL), and tetrakis(triphenylphosphine)palladium (0) (Pd(PPh₃ )₄, 23 mg, 0.02 mmol). The reaction mixture was heated at 110 ⁰C for 20 min under μ-wave. The hot solution was filtered and the solid washed with EtOAc. The organic solution was separated and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried (Na₂SO₄). The solvent was removed in vacuo. The crude product was purified by HPLC. The HPLC fractions containing product were combined and neutralized with saturated NaHCO₃ (50 mL). The free base was extracted with EtOAc (2 x 100 mL). The organic layers were combined and dried (Na₂SO₄). The solvent was removed in vacuo. The residue was dissolved in MeOH (2 mL) and 4.0 M HCl solution (0.3 mL, 1.2 mmol) in dioxane was added. The solution was stirred for 5 min at room temperature and then concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and anhydrous Et₂O (20 mL) was added. The solid was collected by centrifuging. The title compound (3.6 mg, 4%) was afforded as a yellow solid.

[0279] ¹H NMR (500 MHz, DMSO-J₆): δ 2.82 (d, J = 4.5 Hz, 3H), 3.05 (t, J = 11.9 Hz, 2H), 3.15-3.21 (m, 2H), 3.48 (d, J = 11.3 Hz, 2H), 3.73 (d, J = 13.2 Hz, 2H), 6.86-6.87 (m, IH), 7.00 (d, J = 9.1 Hz, 2H), 7.41-7.42 (m, IH), 7.64 (t, J = 1.9 Hz, IH), 7.79 (d, / = 9.1 Hz, 2H), 8.02 (d, J = 7.4 Hz, IH), 8.31 (s, IH), 8.48 (d, J = 7.4 Hz, IH), 9.27 (s, IH), 10.69 (br s, IH), 11.82 (s, IH)

MS (ES+): m/z 466 (M+H)⁺

Example 84 Preparation of Intermediate

53 5-Cyano-4-methylthiophen-2-ylboronic acid (53)

[0280] A solution of 3-methylthiophene-2-carbonitrile ( 1.0 g, 8.1 mmol) in THF ( 15 niL) was cooled to -78 ⁰C under argon (g). A solution of 2.5 M ra-BuLi in hexanes (4.9 rnL, 12.2 mmol) was added dropwise over 5 min. The reaction mixture was stirred at -78 ⁰C for 15 min then triisopropylborate (3.8 mL, 16.2 mmol) was added. The reaction mixture was warmed to room temperature overnight. A solution of IN HCl (15 mL) was added followed by THF (15 mL). The organic layer was washed with brine and dried over MgSO₄. The crude mixture was purified by silica gel chromatography (CH₂Cl₂ZMeOH 100:0 to 85:15 gradient) to afford the title compound as a yellow solid (0.77 g, 57 %).

¹H NMR (500 MHz, DMSO-d₆): δ 2.38 (s, 3H), 7.55 (s, IH)

Example 85 Preparation of 5-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylthiophene-2-carbonitrile

[0281] To a solution of 20 (196 mg, 0.57 mmol) in dimethoxyethane (DME, 10 mL) was added a solution of 53 (95 mg, 0.57 mmol) in EtOH (5 mL), 2.0 M Na₂CO₃ (1.0 mL), and tetrakis(triphenylphosphine)palladium (0) (Pd(PPh₃ )₄, 58 mg, 0.05 mmol). The reaction mixture was heated at 150 ⁰C for 30 min under μ-wave. The hot solution was filtered and the solid washed with EtOAc. The organic solution was separated and the aqueous layer extracted with EtOAc (2 x 50 mL). The combined organic layers were dried (Na₂SO₄). The solvent was removed in vacuo. The crude product was purified by ΗPLC. The ΗPLC fractions containing product were combined and neutralized with saturated NaHCO₃ (50 mL). The free base was extracted with EtOAc (2 x 100 mL). The organic layers were combined and dried (Na₂SO₄). The solvent was removed in vacuo. The residue was dissolved in MeOH (2 mL) and 4.0 M HCl solution (0.3 mL, 1.2 mmol) in dioxane was added. The solution was stirred for 5 min at room temperature and then concentrated in vacuo. The residue was dissolved in MeOH (1 rnL) and anhydrous Et₂O (20 rnL) was added. The solid was collected by centrifuging. The title compound (54 mg, 20%) was afforded as a yellow solid.

[0282] ¹U NMR (500 MHz, DMSO-J₆): δ 2.81 (s, 3H), 3.15-3.18 (m, 4H), 3.49 (d, J = 11.3 Hz, 2H), 3.74 (d, J = 13.2 Hz, 2H), 6.93-6.94 (m, IH), 7.05 (d, J = 8.0 Hz, 2H), 7.38 (br s, IH), 7.75 (d, J = 8.0 Hz, 2H), 8.11 (s, IH), 9.24 (br s, IH), 11.16 (br s, IH), 11.80 (s, IH)

MS (ES+): m/z 430 (M+H)⁺

Example 86 Preparation of 5-(2-(4-(2-(Pyrrolidin-l-yl)ethoxy)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylthiophene-2-carbonitrile

[0283] To a solution of 7 (217 mg, 0.6 mmol) in dimethoxyethane (DME, 10 mL) was added a solution of 53 (152 mg, 0.91 mmol) in EtOH (5 mL), 2.0 M Na₂CO₃ (1.5 mL), and tetrakis(triphenylphosphine)palladium (0) (Pd(PPh₃)₄, 70 mg, 0.06 mmol). The reaction mixture was heated at 150 ⁰C for 30 min under μ-wave. The hot solution was filtered and the solid washed with EtOAc. The organic solution was separated and the aqueous layer extracted with EtOAc (2 x 50 mL). The combined organic layers were dried (Na₂SO₄). The solvent was removed in vacuo. The crude product was purified by ΗPLC. The ΗPLC fractions containing product were combined and neutralized with saturated NaHCO₃ (50 mL). The free base was extracted with EtOAc (2 x 100 mL). The organic layers were combined and dried (Na₂SO₄). The solvent was removed in vacuo. The residue was dissolved in MeOH (2 mL) and 4.0 M HCl solution (0.3 mL, 1.2 mmol) in dioxane was added. The solution was stirred for 5 min at room temperature and then concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and anhydrous Et₂O (20 mL) was added. The solid was collected by centrifuging. The title compound (31 mg, 11%) was afforded as a yellow solid. [0284] ¹H NMR (500 MHz, DMSO-J₆): δ 1.88-1.91 (m, 2H), 1.98-2.03 (m, 2H), 3.09-3.16 (m, 4H), 3.54-3.61 (m, 4H), 4.33 (t, J = 4.9 Hz, 2H), 6.93-6.94 (m, IH), 7.00 (d, J = 8.0 Hz, 2H), 7.38-7.39 (m, IH), 7.76 (d, J= 8.0 Hz, 2H), 8.11 (s, IH), 9.23 (br s, IH), 10.72 (br s, IH), 11.77 (s, IH)

MS (ES+): m/z 445 (M+H)⁺

Example 87 Preparation of Intermediate

B(OH)₂ 54 3-Cyanothiophen-2-yl-2-boronic acid (54)

[0285] To a solution of thiophene-3-carbonitrile (1.5 g, 13.7 mmol) in THF (20 mL) cooled at -78 ⁰C under argon atmosphere was added ra-BuLi (2.5 M in hexanes; 6.6 mL, 16.5 mmol). The mixture was stirred at the same temperature for 15 min and tri-methylborate added (1.9 mL, 16.5 mmol). The resulting mixture was stirred at at -78 ⁰C for 15 min and then stirred at RT for 2 h. The reaction was quenched with IM HCl (10 mL) and concentrated. The residue was taken up in water (40 mL) and extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the crude product recrystallized in EtOAc-hexanes to afford the title compound as a grey solid (1.5 g, 71%).

Example 88 Preparation of 2-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)thiophene-3-carbonitrile

[0286] To a solution of 20 (171 mg, 0.5 mmol) in dimethoxyethane (DME, 10 mL) was added a solution of 54 (84 mg, 0.55 mmol) in EtOH (5 mL), 2.0 M Na₂CO₃ (1.0 mL), and tetrakis(triphenylphosphine)palladium (0) (Pd(PPh₃)₄, 58 mg, 0.05 mmol). The reaction mixture was heated at 150 ⁰C for 30 min under μ-wave. The hot solution was filtered and the solid washed with EtOAc. The organic solution was separated and the aqueous layer extracted with EtOAc (2 x 50 rnL). The combined organic layers were dried (Na₂SO₄). The solvent was removed in vacuo. The crude product was purified by HPLC. The HPLC fractions containing product were combined and neutralized with saturated NaHCO₃ (50 mL). The free base was extracted with EtOAc (2 x 100 mL). The organic layers were combined and dried (Na₂SO₄). The solvent was removed in vacuo. The residue was dissolved in MeOH (2 mL) and 4.0 M HCl solution (0.3 mL, 1.2 mmol) in dioxane was added. The solution was stirred for 5 min at room temperature and then concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and anhydrous Et₂O (20 mL) was added. The solid was collected by centrifuging. The title compound (15 mg, 7%) was afforded as a yellow solid.

[0287] ¹H NMR (500 MHz, DMSO-J₆): δ 2.81 (d, J= 3.3 Hz, 3H), 3.07 (t, J= 11.9 Hz, 2H), 3.14-3.18 (m, 2H), 3.49 (d, J = 11.8 Hz, 2H), 3.71 (d, J = 13.0 Hz, 2H), 6.62-6.63 (m, IH), 6.97 (d, / = 9.1 Hz, 2H), 7.35-7.36 (m, IH), 7.68 (d, J = 5.2 Hz, IH), 7.78 (d, / = 9.1 Hz, 2H), 9.20 (br s, IH), 10.85 (br s, IH), 11.81 (s, IH)

MS (ES+): m/z 416 (M+H)⁺

Example 89 2-(2-(3-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-<i]pyrimidin-4- yl)thiophene-3-carbonitrile

[0288] To a solution of 47 (120 mg, 0.35 mmol) in dimethoxyethane (DME, 10 mL) was added a solution of 54 (64 mg, 0.42 mmol) in EtOH (5 mL), 2.0 M Na₂CO₃ (1.0 mL), and tetrakis(triphenylphosphine)palladium (0) (Pd(PPh₃ )₄, 58 mg, 0.05 mmol). The reaction mixture was heated at 150 ⁰C for 30 min under μ-wave. The hot solution was filtered and the solid washed with EtOAc. The organic solution was separated and the aqueous layer extracted with EtOAc (2 x 50 mL). The combined organic layers were dried (Na₂SO₄). The solvent was removed in vacuo. The crude product was purified by HPLC. The HPLC fractions containing product were combined and neutralized with saturated NaHCO₃ (50 rnL). The free base was extracted with EtOAc (2 x 100 rnL). The organic layers were combined and dried (Na₂SO₄). The solvent was removed in vacuo. The residue was dissolved in MeOH (2 mL) and 4.0 M HCl solution (0.3 mL, 1.2 mmol) in dioxane was added. The solution was stirred for 5 min at room temperature and then concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and anhydrous Et₂O (20 mL) was added. The solid was collected by centrifuging. The title compound (19 mg, 12%) was afforded as a yellow solid.

[0289] ¹H NMR (500 MHz, DMSO-J₆): δ 2.81 (d, J = 3.3 Hz, 3H), 3.15-3.20 (m, 4H), 3.49 (d, J = 6.0 Hz, 2H), 3.78 (d, J = 8.9 Hz, 2H), 6.60 (dd, J = 8.2, 2.0 Hz, IH), 6.64-6.65 (m, IH), 7.15 (t, J = 8.2 Hz, IH), 7.40-7.41 (m, IH), 7.43 (dd, J= 8.0, 1.3 Hz, IH), 7.65 (t, J = 1.9 Hz, IH), 7.69 (d, J = 5.3 Hz, IH), 8.08 (d, J = 5.3 Hz, IH), 9.25 (s, IH), 11.09 (br s, IH), 11.95 (s, IH)

MS (ES+): m/z 416 (M+H)⁺

Example 90 Preparation of Intermediates

55

/er/-Butyl[(/er/-butoxycarbonyl)amino]{[4-(morpholin-4-ylmethyl)phenyl]amino} methylidene] carbamate (55)

[0290] A mixture of (fer^-butoxycarbonylimino-pyrazol-l-yl-methy^-carbamic acid tert- butyl ester (3.1 g, 10.0 mmol) and 4-(moφholinomethyl)benzenamine (1.92 g, 10.0 mmol) in DMF (10 mL) was stirred at room temperature for 17 h. The reaction mixture was concentrated and the residue taken in water (50 mL). The resulting solid was filtered, washed with water and dried under high vacuum to afford the title compound as an off white solid. The material was used in the next step without purification.

56 (4-(Morpholinomethyl)phenyl)guanidine TFA salt (56)

[0291] A solution of 55 in 50% TFA/DCM (10 niL) was stirred at room temperature for 17 h. The solution was concentrated to afford the title compound, which was used in the next step without purification.

57 2-(4-(Morpholinomethyl)phenylamino)-7H-pyrrolo[2,3-rf]pyrimidin-4-ol (57)

[0292] To a microwave reaction tube was charged with 56 (10.0 mmol), 2-cyano-4,4- diethoxy-butyric acid ethyl ester (2.3 g, 10.0 mmol) and NaOMe (25% by wt in MeOH; 15 mL) in EtOH (5 mL). The reaction tube was sealed and the solution irradiated with microwave at 160 ⁰C for 30 min. After cooling to room temperature, the mixture was concentrated. The residue was taken up in water (10 mL) and the pH adjusted to 1 with 6M of HCl. The resulting solution was stirred at room temperature for 25 min and then the pH adjusted to 9 with concentrated 10% NaOH. The resulting solid was filtered, washed with water and dried under high vacuum to afford the title compound as a brown solid. The material was used in the next step without purification.

58 4-Chloro-N-(4-(morpholinomethyl)phenyl)-7H-pyrrolo[2,3-rf]pyrimidin-2-amine

(58)

[0293] A solution of 57 (10 mmol) in POCl₃ (10 mL) was heated at 120 ⁰C for 20 min. After cooling to room temperature, the excess POCl₃ was removed in vacuo. The resulting dark residue was added to ice water slowly and the pH adjusted to 9-10 with 10% NaOH. The resulting solid was filtered, washed with water and dried under high vacuum to afford the title compound as a brown solid (1.0 g, 29%). The material was used in the next step without purification.

Exmaple 91 Preparation of 4-(5-(3,5-Dimethylisoxazol-4-yl)thiophen-2-yl)-/V-(4- (morpholinomethyl)phenyl)-7H-pyrrolo[2,3-J]pyrimidin-2-amine

[0294] To a solution of 58 (82 mg, 0.24 mmol) in dimethoxyethane (DME, 10 mL) was added a solution of 35 (60 mg, 0.27 mmol) in EtOH (5 mL), 2.0 M Na₂CO₃ (1.0 mL), and tetrakis- (triphenylphosphine)palladium (0) (Pd(PPh₃)₄, 35 mg, 0.03 mmol). The reaction mixture was heated at 150 ⁰C for 30 min under μ-wave. The hot solution was filtered and the solid washed with EtOAc. The organic solution was separated and the aqueous layer extracted with EtOAc (2 x 50 mL). The combined organic layers were dried (Na₂SO₄). The solvent was removed in vacuo. The crude product was purified by ΗPLC. The ΗPLC fractions containing product were combined and neutralized with saturated NaHCO₃ (50 mL). The free base was extracted with EtOAc (2 x 100 mL). The organic layers were combined and dried (Na₂SO₄). The solvent was removed in vacuo. The residue was dissolved in MeOH (2 mL) and 4.0 M HCl solution (0.3 mL, 1.2 mmol) in dioxane was added. The solution was stirred for 5 min at room temperature and then concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and anhydrous Et₂O (20 mL) was added. The solid was collected by centrifuging. The title compound (35 mg, 29%) was afforded as a yellow solid.

[0295] ¹H NMR (500 MHz, DMSO-J₆): δ 2.42 (s, 3H), 2.62 (s, 3H), 3.02-3.08 (m, 2H), 3.23 (d, J = 12.2 Hz, 2H), 3.74-3.78 (m, 2H), 3.93-3.95 (m, 2H), 4.25 (d, J = 5.2 Hz, 2H), 6.92-6.93 (m, IH), 7.36-7.37 (m, IH), 7.38 (d, J = 3.9 Hz, IH), 7.49 (d, J = 8.6 Hz, 2H), 8.00 (d, J = 8.6 Hz, 2H), 8.15 (d, J = 3.9 Hz, IH), 9.53 (s, IH), 10.78 (br s, IH), 11.78 (s, IH)

MS (ES+): m/z 487 (M+H)⁺ Example 92 Preparation of 4-(Benzo[b]thiophen-2-yl)-N-(4-(morpholinomethyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine hydrochloride

[0296] To a solution of 58 (82 mg, 0.24 mmol) in dimethoxyethane (DME, 10 rnL) was added a solution of benzo[b]thiophen-2-yl-2-boronic acid (47 mg, 0.27 mmol) in EtOH (5 mL), 2.0 M Na₂CO₃ (1.0 rnL), and tetrakis- (triphenylphosphine)palladium (0) (Pd(PPh₃ )₄, 35 mg, 0.03 mmol). The reaction mixture was heated at 150 ⁰C for 30 min under μ-wave. The hot solution was filtered and the solid washed with EtOAc. The organic solution was separated and the aqueous layer extracted with EtOAc (2 x 50 mL). The combined organic layers were dried (Na₂SO₄). The solvent was removed in vacuo. The crude product was purified by ΗPLC. The ΗPLC fractions containing product were combined and neutralized with saturated NaHCO₃ (50 mL). The free base was extracted with EtOAc (2 x 100 mL). The organic layers were combined and dried (Na₂SO₄). The solvent was removed in vacuo. The residue was dissolved in MeOH (2 mL) and 4.0 M HCl solution (0.3 mL, 1.2 mmol) in dioxane was added. The solution was stirred for 5 min at room temperature and then concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and anhydrous Et₂O (20 mL) was added. The solid was collected by centrifuging. The title compound (21 mg, 18%) was afforded as a yellow solid.

[0297] ¹H NMR (500 MHz, DMSO-J₆): δ 3.03-3.10 (m, 2H), 3.24 (d, J = 12.1 Hz, 2H), 3.81 (t, J = 11.6 Hz, 2H), 3.93-3.96 (m, 2H), 4.26 (d, J = 5.2 Hz, 2H), 7.05-7.06 (m, IH), 7.44- 7.48 (m, 3H), 7.54 (d, J = 8.7 Hz, 2H), 8.01-8.06 (m, 4H), 8.52 (s, IH), 9.59 (s, IH), 11.07 (br s, IH), 11.86 (s, IH)

MS (ES+): m/z 442 (M+H)⁺

Example 93 Preparation of 2-(2-(4-(Morpholinomethyl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)benzo[b]thiophene-6-carbonitrile

[0298] To a solution of 58 (82 mg, 0.24 mmol) in dimethoxyethane (DME, 10 niL) was added a solution of 30 (55 mg, 0.27 mmol) in EtOH (5 mL), 2.0 M Na₂CO₃ (1.0 mL), and tetrakis- (triphenylphosphine)palladium (0) (Pd(PPh₃)₄, 35 mg, 0.03 mmol). The reaction mixture was heated at 150 ⁰C for 30 min under μ-wave. The hot solution was filtered and the solid washed with EtOAc. The organic solution was separated and the aqueous layer extracted with EtOAc (2 x 50 mL). The combined organic layers were dried (Na₂SO₄). The solvent was removed in vacuo. The crude product was purified by HPLC. The HPLC fractions containing product were combined and neutralized with saturated NaHCO₃ (50 mL). The free base was extracted with EtOAc (2 x 100 mL). The organic layers were combined and dried (Na₂SO₄). The solvent was removed in vacuo. The residue was dissolved in MeOH (2 mL) and 4.0 M HCl solution (0.3 mL, 1.2 mmol) in dioxane was added. The solution was stirred for 5 min at room temperature and then concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and anhydrous Et₂O (20 mL) was added. The solid was collected by centrifuging. The title compound (12 mg, 10%) was afforded as a yellow solid.

[0299] ¹H NMR (500 MHz, DMSO-J₆): δ 3.05-3.12 (m, 2H), 3.26 (d, J = IlA Hz, 2H), 3.74 (t, J = 11.6 Hz, 2H), 3.95-3.97 (m, 2H), 4.28 (d, J= 5.1 Hz, 2H), 7.07-7.09 (m, IH), 7.49- 7.51 (m, 3H), 7.83 (dd, J = 8.2, 1.4 Hz, IH), 8.02 (d, J = 8.7 Hz, 2H), 8.17 (d, J = 8.3 Hz, 2H), 8.64 (s, IH), 8.69 (s, IH), 9.65 (s, IH), 10.55 (br s, IH), 11.91 (s, IH)

MS (ES+): m/z 467 (M+H)⁺

Example 94 Preparation of 4-(5-Methylbenzo[b]thiophen-2-yl)-N-(4- (morpholinomethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine

[0300] To a solution of 58 (82 mg, 0.24 mmol) in dimethoxyethane (DME, 10 niL) was added a solution of 5-methylbenzo[b]thiophen-2-yl-2-boronic acid (52 mg, 0.27 mmol) in EtOH (5 mL), 2.0 M Na₂CO₃ (1.0 mL), and tetrakis- (triphenylphosphine)palladium (0) (Pd(PPh₃)₄, 35 mg, 0.03 mmol). The reaction mixture was heated at 150 ⁰C for 30 min under μ-wave. The hot solution was filtered and the solid washed with EtOAc. The organic solution was separated and the aqueous layer extracted with EtOAc (2 x 50 mL). The combined organic layers were dried (Na₂SO₄). The solvent was removed in vacuo. The crude product was purified by HPLC. The HPLC fractions containing product were combined and neutralized with saturated NaHCO₃ (50 mL). The free base was extracted with EtOAc (2 x

100 mL). The organic layers were combined and dried (Na₂SO₄). The solvent was removed in vacuo. The residue was dissolved in MeOH (2 mL) and 4.0 M HCl solution (0.3 mL, 1.2 mmol) in dioxane was added. The solution was stirred for 5 min at room temperature and then concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and anhydrous Et₂O (20 mL) was added. The solid was collected by centrifuging. The title compound (17 mg, 15%) was afforded as a yellow solid.

[0301] ¹H NMR (500 MHz, DMSO-J₆): δ 2.46 (s, 3H), 3.03-3.10 (m, 2H), 3.25 (d, J = 12.1 Hz, 2H), 3.78 (t, J = 11.6 Hz, 2H), 3.93-3.96 (m, 2H), 4.26 (d, J = 5.1 Hz, 2H), 7.03-7.04 (m, IH), 7.30 (dd, J = 8.4, 1.2 Hz, lH),7.43-7.44 (m, IH), 7.52 (d, J = 8.6 Hz, 2H), 7.81 (s, IH), 7.93 (d, J = 8.2 Hz, IH), 8.03 (d, J = 8.6 Hz, 2H), 8.42 (s, IH), 9.58 (s, IH), 10.95 (br s, IH),

11.84 (s, IH)

MS (ES+): m/z 456 (M+H)⁺

Example 95 Preparation of 4-(Benzo[b]thiophen-2-yl)-N-(4-((piperidin-l-yl)methyl)phenyl)- 7H-pyrrolo[2,3-d]pyrimidin-2-amine

[0302] To a solution of 24 (80 mg, 0.28 mmol) in 1,4-dioxane (10 niL) and DMF (5 niL) was added 4-((piperidin-l-yl)methyl)benzenamine (54 mg, 0.28 mmol), KO^-Bu (112 mg, 1.0 mmol), Pd₂(dba)₃ (20 mg, 0.02 mmol), and 1.0 M tri-te/t-butylphosphine in toluene (0.06 mL, 0.06 mmol). The reaction mixture was heated at 150 ⁰C for 20 min under μ-wave. The solid was filtered off and the filtrate washed with brine (1 x 50 mL). The organic solution was separated and dried (Na₂SO₄). The solvent was removed in vacuo. The crude product was purified by HPLC. The HPLC fractions containing product were combined and neutralized with saturated NaHCO₃ (50 mL). The free base was extracted with EtOAc (2 x 100 mL). The organic layers were combined and dried (Na₂SO₄). The solvent was removed in vacuo. The residue was dissolved in MeOH (2 mL) and 4.0 M HCl solution (0.2 mL, 0.8 mmol) in dioxane was added. The solution was stirred for 5 min at room temperature and then concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and anhydrous Et₂O (20 mL) was added. The solid was collected by centrifuging. The title compound (18 mg, 14%) was afforded as a yellow solid.

[0303] ¹H NMR (500 MHz, DMSO-J₆): δ 1.30-1.37 (m, IH), 1.66-1.71 (m, IH), 1.75-1.82 (m, 4H), 3.29 (d, J = 11.5 Hz, 2H), 4.17 (d, J = 5.1 Hz, 2H), 7.05-7.06 (m, IH), 7.43-7.45 (m, IH), 7.46-7.48 (m, 2H), 7.54 (d, J = 8.6 Hz, 2H), 8.01-8.07 (m, 4H), 8.52 (s, IH), 9.57 (s, IH), 10.51 (br s, IH), 11.87 (s, IH)

MS (ES+): m/z 440 (M+H)⁺

Example 96 Preparation of 4-(Benzo[b]thiophen-2-yl)-N-(4-((2-methyl-lH-imidazol-l- yl)methyl)phenyl)-7H-pyrrolo[2,3-J]pyrimidin-2-amine

[0304] To a solution of 24 (80 mg, 0.28 mmol) in 1,4-dioxane (10 niL) and DMF (5 niL) was added 4-((2-methyl-lH-imidazol-l-yl)methyl)benzenamine (58 mg, 0.31 mmol), KO^-Bu (112 mg, 1.0 mmol), Pd₂(dba)₃ (20 mg, 0.02 mmol), and 1.0 M tri-tert-butylphosphine in toluene (0.06 mL, 0.06 mmol). The reaction mixture was heated at 150 ⁰C for 20 min under μ- wave. The solid was filtered off and the filtrate washed with brine (1 x 50 mL). The organic solution was separated and dried (Na₂SO₄). The solvent was removed in vacuo. The crude product was purified by ΗPLC. The ΗPLC fractions containing product were combined and neutralized with saturated NaHCO₃ (50 mL). The free base was extracted with EtOAc (2 x 10O mL). The organic layers were combined and dried (Na₂SO₄). The solvent was removed in vacuo. The residue was dissolved in MeOH (2 mL) and 4.0 M HCl solution (0.2 mL, 0.8 mmol) in dioxane was added. The solution was stirred for 5 min at room temperature and then concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and anhydrous Et₂O (20 mL) was added. The solid was collected by centrifuging. The title compound (23 mg, 17%) was afforded as a yellow solid.

[0305] ¹H NMR (500 MHz, DMSO-J₆): δ 2.66 (s, 3H), 5.31 (s, 2H), 7.04-7.05 (m, IH), 7.35 (d, J = 8.7 Hz, 2H), 7.42-7.43 (m, IH), 7.45-7.47 (m, 2H), 7.59 (d, J = 1.9 Hz, IH), 7.69 (d, J = 2.0 Hz, IH), 7.98 (d, J = 8.7 Hz, 2H), 8.01-8.06 (m, 2H), 8.51 (s, IH), 9.52 (s, IH), 11.83 (s, IH), 14.56 (s, IH)

MS (ES+): m/z 437 (M+H)⁺

Example 97 Preparation of Intermediate

59

5-(2-(4-((2-methyl-lH-imidazol-l-yl)methyl)phenylamino)-7H-pyrrolo[2,3- rf]pyrimidin-4-yl)thiophene-2-carboxylic acid (59)

[0306] A mixture of S-boronothiophene-l-carboxylic acid (211 mg, 1.2 mmol), 39 (363 mg, 1.1 mmol), Pd(PPh₃)₄ (98 mg, 0.08 mmol), DME (4.3 mL), EtOH (4.3 mL), and 2M Na₂CO₃ (2.1 mL, 4.2 mmol) was irradiated in the microwave at 110 ⁰C for 20 min. The solids were filtered, the filtrate was concentrated in vacuo, and the residue was crystallized in DCM- MeOH/hexanes to afford the title compound as an orange-brown crude solid (324 mg, 70%). The material was used as is for the next reaction.

MS (ES+): m/z 431 (M+H)⁺

Example 98 Preparation of N-fert-Butyl-5-(2-(4-((2-methyl-lH-imidazol-l- yl)methyl)phenylamino)-7H-pyrrolo[2,3-(i]pyrimidin-4-yl)thiophene-2-carboxamide

[0307] To a slurry of 59 (99 mg, 0.23 mmol) in DCM (2.3 mL) was added oxalyl chloride (0.21 mL, 2.35 mmol) and DMF (0.1 mL). The reaction was stirred for 3.5 h. 2- Methylpropan-2-amine (2.5 mL) was very slowly and carefully added to the reaction mixture and was stirred for 15 min. The crude reaction was concentrated in vacuo and the residue purified by preparatory ΗPLC to afford the title compound as a yellow solid (26 mg, 23%). [0308] ¹H NMR (500 MHz, DMSO-J₆) δ 1.40 (s, 9H), 2.27 (s, 3H), 5.06 (s, 2H), 6.75 (s, IH), 6.89 (dd, J = 3.6, 1.6 Hz, IH), 7.12 (d, J = 9.0 Hz, 3H), 7.34 (dd, J = 3.4, 2.4 Hz, IH), 7.86 (d, J= 8.6 Hz, 2H), 7.92 (t, J= 4.2 Hz, 2H), 8.04 (d, J= 4.0 Hz, IH), 9.32 (s, IH), 11.69 (s, IH)

MS (ES+): m/z 404 (M+H)⁺

Example 99 Preparation of Intermediates

(4-Methylpiperazin-l-yl)(3-nitrophenyl)methanone (60)

[0309] To a solution of 3-nitrobenzoyl chloride (3.72 g, 20 mmol) in THF (30 mL) was added dropwise 1-methylpiperazine (6.7 mL, 60 mmol). The reaction was stirred for 20 min and was quenched with 30 mL water. The reaction mixture was extracted with ethyl acetate (4x30 mL) and the combined ethyl acetate layers were washed with brine (30 mL). The brine was back extracted with ethyl acetate (2x30 mL) and all the organic layers were combined, dried (MgSO₄), filtered, and concentrated in vacuo to a dark yellow oil that solidified on standing (5.05 g, 101%, contains ethyl acetate in NMR).

[0310] ¹H NMR (500 MHz, DMSO-J₆) δ 2.20 (s, 3H), 2.27 (br s, 2H), 2.38 (br s, 2H), 3.31 (br s, 2H), 3.64 (br s, 2H), 7.74 (t, J = 7.9 Hz, IH), 7.85 (dt, J = 7.7, 1.1 Hz, IH), 8.18 (t, J = 1.9 Hz, IH), 8.30 (ddd, J = 8.1, 2.2, 0.8 Hz, IH)

MS (ES+): m/z 250 (M+H)⁺

61 (3-Aminophenyl)(4-methylpiperazin-l-yl)methanone (61)

[0311] To an argon flushed solution of 60 (4.99 g, 20 mmol) in methanol (100 mL) was added 10% Pd/C (5.00 g). The suspension was flushed with hydrogen and stirred under an atmosphere of hydrogen for 2 h. The reaction was flushed with argon, filtered through celite, and concentrated in vacuo to afford the title compound as an colorless oil that solidified on standing to a white solid (4.07 g, 93%).

[0312] ¹H NMR (500 MHz, DMSO-J₆) δ 2.18 (s, 3H), 2.24-2.35 (m, 4H), 3.33 (br s, 2H), 3.66 (br s, 2H), 5.25 (s, 2H), 6.43 (d, J = 7.5 Hz, IH), 6.52 (t, J = 1.8 Hz, IH), 6.59 (dt, J = 8.9, 1.2 Hz, IH), 7.04 (t, J= 7.8 Hz, IH)

MS (ES+): m/z 220 (M+H)⁺

Example 100 Preparation of (4-Methylpiperazin-l-yl)(3-(4-(4-methylthiophen-2-yl)-7H- pyrrolo[2,3-J]pyrimidin-2-ylamino)phenyl)methanone

[0313] A mixture of 9 (499 mg, 1.2 mmol), 61 (328 mg, 1.5 mmol), Pd(OAc)₂ (27 mg, 0.1 mmol), TEA (1.7 mL, 12.1 mmol), IM P(J-Bu)₃ (0.25 mL, 0.25 mmol), in DMF (8 mL) was irradiated in the microwave at 180 ⁰C for 20 min. The solids were filtered, and the filtrate was purified by preparatory ΗPLC. The resulting beige solid (230 mg) was taken up in methanol and treated with Cs₂CO₃ (1.30 g, 3.99 mmol) at 60 ⁰C for 30 min. The crude material was concentrated in vacuo and purified by flash chromatography (0-20% methanol in DCM) and precipitated from acetone/hexanes to afford the title compound as a yellow solid (62 mg, 12%).

[0314] ¹H NMR (500 MHz, DMSO-J₆) δ 2.18 (s, 3H), 2.27 (br s, 2H), 2.33 (s, 3H), 2.37 (br s, 2H), 3.35-3.40 (m, 2H), 3.64 (br s, 2H), 6.85-6.89 (m, 2H), 7.30-7.35 (m, 2H), 7.40 (s, IH), 7.90 (d, J = 8.2 Hz, IH), 7.93 (s, IH), 8.03 (s, IH), 9.40 (s, IH), 11.68 (s, IH)

MS (ES+): m/z 433 (M+H)⁺

Example 101 Preparation of Intermediates

62 N-før/-Butyl-3-methylthiophene-2-carboxamide (62)

[0315] 2-Methylpropan-2-amine (10 niL, 95.2 mmol) was cooled to 0 ⁰C. 3- Methylthiophene-2-carbonyl chloride (1.2 niL, 9.8 mmol) was added very slowly and carefully to the cooled amine. Upon conclusion of the addition, the reaction was warmed to room temperature and stirred for 30 min. Water (30 mL) and DCM (30 mL) was added and the mixture was stirred 16 h. The phases were separated and the organic layer was washed with IN HCl (10 mL), water, (10 mL), brine (10 mL), dried (MgSO₄), filtered, and concentrated in vacuo to afford the title compound as an off white solid (1.71 g, 88%).

[0316] ¹H NMR (500 MHz, DMSO-J₆) δ 1.35 (s, 9H), 2.36 (s, 3H), 6.92 (d, J = 5.0 Hz, IH), 7.33 (br s, IH), 7.51 (d, J = 5.0 Hz, IH)

MS (ES+): m/z 198 (M+H)⁺

63

5-(tør/-Butylcarbamoyl)-4-methylthiophen-2-ylboronic acid (63)

[0317] To a cooled (-78 ⁰C) solution of 62 (795 mg, 4.03 mmol) in THF (20 mL) was added dropwise 1.5 M LDA (6.7 mL, 10.05 mmol). The solution was warmed to -10 ⁰C and triisopropyl borate (1.4 mL, 6.09 mmol) was added. The solution was warmed to room temperature and stirred for 66 h. The reaction solution was washed with IN HCl (20 mL) and the resulting aqueous layer was back extracted with ethyl acetate (4x20 mL). The combined organic layers were washed with brine (20 mL) and the brine was again back extracted with ethyl acetate (2x20 mL). All the organic layers were combined, dried (MgSO₄), and concentrated in vacuo. The crude residue was purified using flash chromatography (0-20% MeOH in DCM) to afford the title compound as a light brown syrup (512 mg, 53%).

MS (ES+): m/z 242 (M+H)⁺

Example 102 Preparation of Λ^te/t-Butyl-3-methyl-5-(2-(4-(2-(pyrrolidin-l- yl)ethoxy)phenylamino)-7H-pyrrolo[2,3-(i]pyrimidin-4-yl)thiophene-2-carboxamide

[0318] A mixture of 63 (133 mg, 0.55 mmol), 7 (180 mg, 0.50 mmol), Pd(PPh₃)₄ (58 mg, 0.05 mmol), DME (2 mL), EtOH (2 mL), and 2M Na₂CO₃ (1 mL, 2 mmol) was irradiated in the microwave at 110 ⁰C for 20 min. The crude reaction mixture was partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was separated, dried (Na₂SO₄), filtered, concentrated in vacuo, and the residue purified by ΗPLC. The fractions were neutralized with saturated NaHCO₃ and extracted with EtOAc. The organic layers were concentrated in vacuo and the residue was precipitated from ethyl acetate/hexanes to afford the title compound as a yellow solid (63 mg, 24%).

[0319] ¹H NMR (500 MHz, DMSO-J₆) δ 1.38 (s, 9H), 1.70 (br s, 4H), 2.45 (s, 3H), 2.57 (br s, 4H), 2.82 (br s, 2H), 4.05 (t, J = 5.9 Hz, 2H), 6.86 (dd, J = 3.7, 1.8 Hz, IH), 6.89 (d, J = 9.0 Hz, 2H), 7.28 (dd, J = 3.6, 2.3 Hz, IH), 7.58 (s, IH), 7.75 (d, J = 9.1 Hz, 2H), 7.87 (s, IH), 9.03 (s, IH)

MS (ES+): m/z 519 (M+H)⁺

Example 103 Preparation of Intermediates

64 5-(2-Chloro-7-tosyl-7H-pyrrolo[2,3-rf]pyrimidin-4-yl)thiophene-2-carbonitrile (64)

[0320] A mixture of 8 (0.34 g, 1.0 mmol), S-cyanothiophen-l-yM-boronic acid (0.18 g, 1.2 mmol), Pd(PPh₃)₄ (12 mg, 0.01 mmol) and Na₂CO₃ (0.32 g, 3 mmol) in anhydrous DMF (25 mL) was degassed with argon for 2 min and then heated at 125 ⁰C for 5 h. After cooling to room temperature, the solvent was removed by rotovap. The crude product was then purified by silica gel column with 2% CH₃OH/CHC1₃ as an eluent to yield a pale yellow solid (70 mg, 17%).

[0321] ¹H NMR (500 MHz, CDCl₃): δ 2.42 (s, 3H), 6.89 (d, J = 4.0 Hz, IH), 7.36 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 4.0 Hz, 2H), 7.85 (dd, J = 4.0, 2.4 Hz, 2H), 8.14 (d, J = 10.4 Hz, 2H)

65 5-(2-(4-(lH-Imidazol-l-yl)phenylamino)-7-tosyl-7H-pyrrolo[2,3-rf]pyrimidin-4- yl)thiophene-2-carbonitrile (65)

[0322] A suspension of 64 (70 mg, 0.17 mmol), 4-(lH-imidazol-l-yl)benzenamine (32 mg, 0.20 mmol), Pd₂(dba)₃ (20 mg, 0.02 mmol), Xantphos (20 mg, 0.03 mmol) and cesium carbonate (0.17 g, 0.52 mmol) in anhydrous DMF (5 mL) was degassed with argon for 2 min then heated in a sealed tube at 135 ⁰C for 3 h. After cooling to room temperature, the solvent was removed by rotovap and the resulting mixture was purified by silica gel with 5% CH₃OH/CHCI₃ as an eluent to afford the title compound (50 mg, 55%) as a white solid.

[0323] ¹H NMR (500 MHz, DMSO-J₆): δ 7.11 (s, IH), 7.31 (d, J = 4.2 Hz, IH), 7.43 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 9.0 Hz, 2H), 7.77 (s, IH), 7.82 (d, J = 4.1 Hz, IH), 8.03 (d, J = 9.0 Hz, 2H), 8.06 (d, J = 8.2 Hz, 2H), 8.12 (d, J = 4.2 Hz, IH), 8.24 (d, J = 4.1 Hz, IH), 8.26 (s, IH), 10.04 (s, IH)

Example 104 Preparation of 5-(2-(4-(lH-Imidazol-l-yl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)thiophene-2-carbonitrile

[0324] A mixture of 65 (50 mg, 0.09 mmol) and Cs₂CO₃ (0.15 g, 0.46 mmol) in methanol (15 mL) was refluxed for 5 h. After cooling to room temperature, the solvent was removed by rotovap and the resulting mixture purified by silica gel with 5% CΗ₃OΗ/CΗCI₃ as an eluent to afford the title compound as a yellow solid.

[0325] ¹H NMR (500 MHz, DMSO-J₆): δ 6.97 (s, IH), 7.09 (br s, IH), 7.37 (br s, IH), 7.58 (d, J = 8.4 Hz, 2H), 7.69 (br s, IH), 7.99 (d, J = 8.6 Hz, 2H), 8.11 (d, J = 3.7 Hz, IH), 8.18 (br s, IH), 8.21 (d, J = 3.7 Hz, IH), 9.60 (s, IH), 11.89 (s, IH)

MS (ES+): m/z 384 (M+H)⁺

Example 105 Preparation of Intermediate

66

^r/-Butyl 4-(4-(4-(4-methylthiophen-2-yl)-7-tosyl-7H-pyrrolo[2,3-rf]pyrimidin-2- ylamino)benzyl)piperazine-l-carboxylate (66)

[0326] A mixture of 9 (0.25 g, 0.62 mmol), tert-butyl 4-(4-aminobenzyl)piperazine-l- carboxylate (0.22 g, 0.76 mmol), Pd₂(dba)₃ (57 mg, 0.06 mmol), Xantphos (72 mg, 0.12 mmol) and Cs₂CO₃ (0.61 g, 1.88 mmol) in anhydrous DMF (25 mL) was degassed with argon for 2 min and then heated at 125 ⁰C for 2 h. After cooling to room temperature, the solvent was removed by rotovap. The crude product was then purified by silica gel column with 10% CH₃OH/CHC1₃ as an eluent to yield a yellow solid (90 mg, 22%).

[0327] ¹H NMR (500 MHz, DMSO-J₆): δ 1.41 (s, 9H), 2.31 (s, 3H), 2.33 (s, 3H), 2.90-3.05 (m, 2H), 3.20-3.40 (m, 4H), 3.90-4.10 (m, 2H), 4.25-4.35 (m, 2H), 7.26 (d, J = 4.0 Hz, IH), 7.36 (d, J = 8.5 Hz, 2H), 7.48 (s, IH), 7.56 (d, J = 8.6 Hz, 2H), 7.74 (d, J = 4.1 Hz, IH), 7.95- 8.10 (m, 5H), 9.88 (s, IH), 10.94 (br s, IH)

Example 106 Preparation of 4-(4-Methylthiophen-2-yl)-N-(4-((piperazin-l-yl)methyl)phenyl)- 7H-pyrrolo[2,3-d]pyrimidin-2-amine

[0328] A mixture of 66 (90 mg, 0.14 mmol), Cs₂CO₃ (0.15 g, 0.46 mmol) in CH₃OH (25 mL) and CHCl₃ (5 mL) was heated to reflux for 5 h. After cooling to room temperature, the solvent was removed by rotovap. The crude product was then purified by silica gel column with 10% CH₃OH/CHC1₃ as an eluent to yield a yellow solid. The above yellow solid was dis solved in CHCl₃ (20 niL) and 4M HCl in dioxane (4 niL) and stirred at room temperature for 2 h. The precipitate was further purified by silica gel column with 35% CH₃OH/CHCI₃ with ammonia as an eluent to yield a yellow solid (10 mg, 18% in 2 steps).

[0329] ¹H NMR (500 MHz, DMSO-J₆): δ 2.00-2.50 (m, 7H), 2.50-2.80 (br s, 4H), 3.30 (br s, 2H), 6.85 (br s, IH), 7.16 (d, J = 8.4 Hz, 2H), 7.28 (br s, IH), 7.39 (br s, IH), 7.82 (d, J = 8.6 Hz, 2H), 7.91 (br s, IH), 9.16 (s, IH), 11.60 (br s, IH)

MS (ES+): m/z 405 (M+H)⁺

Example 107 Preparation of Intermediate

67 l.(4.(4.(4.(4.Methylthiophen-2-yl)-7-tosyl-7H-pyrrolo[2,3-rf]pyrimidin-2- ylamino)benzyl)piperazin-l-yl)ethanone (67)

[0330] A mixture of l-(bromomethyl)-4-nitrobenzene (2.16 g, 10 mmol), l-(piperazin-l- yl)ethanone (3.2 g, 25 mmol), Na₂CO₃ (2.12 g, 20 mmol) in DMF (50 mL) was heated to 80 ⁰C for 2 h. After cooling to room temperature, the solvent was removed by rotovap. The crude product was dissolved in ethyl acetate (100 mL) and washed by saturated NaHCO₃ (3 x 25 mL). The organic phase was dried over Na₂SO₄ and the salt was removed by filtration. The solvent was removed by rotovap to yield a yellow oil. The above crude oil and 10% Pd/C (50 mg) in ethyl acetate (100 mL) was hydrogenated under a H₂ balloon for 3 h. The Pd/C was removed by filtration and the solvent concentrated by rotovap. The crude product was purified by silica gel column with 10% CH₃OH/CHCI₃ as an eluent to yield 1-(A-(A- aminobenzyl)piperazin-l-yl)ethanone as a colorless oil (0.50 g, 22% in 2 steps). A mixture of 9 (0.17 g, 0.50 mmol), l-(4-(4-aminobenzyl)piperazin-l-yl)ethanone (0.15 g, 0.64 mmol), Pd₂(dba)₃ (50 mg, 0.05 mmol), Xantphos (60 mg, 0.10 mmol) and Cs₂CO₃ (0.49 g, 1.5 mmol) in anhydrous DMF (50 mL) was degassed with argon for 2 min and then heated at 130 ⁰C for 2 h. After cooling to room temperature, the solvent was removed by rotovap. The crude product was then purified by silica gel column with 10% CH₃OH/CHCI₃ as an eluent to yield a yellow oil. A bright yellow solid was obtained after titrated with HCl (80 mg, 30%).

[0331] ¹H NMR (500 MHz, DMSO-J₆): δ 2.04 (s, 3H), 2.31 (s, 3H), 2.36 (s, 3H), 2.80-2.90 (m, IH), 2.95-3.05 (m, 2H), 3.30-3.40 (m, 4H), 3.90-4.10 (m, IH), 4.20-4.30 (m, 2H), 4.40- 4.50 (m, IH), 7.26 (d, J = 4.0 Hz, IH), 7.43 (d, J = 8.3 Hz, 2H), 7.48 (s, IH), 7.55 (d, J = 8.6 Hz, 2H), 7.74 (d, J = 4.1 Hz, IH), 7.90-8.10 (m, 5H), 9.89 (s, IH), 10.92 (br s, IH)

Example 108 Preparation of l-(4-((4-(4-(4-Methylthiophen-2-yl)-7H-pyrrolo[2,3-J]pyrimidin- 2-ylamino)phenyl)methyl)piperazin- 1 -yl)ethanone

[0332] A mixture of 67 (80 mg, 0.15 mmol) and Cs₂CO₃ (0.15 g, 0.46 mmol) in methanol (25 mL) was refluxed for 2 h. After cooling to room temperature, the solvent was removed by rotovap and the resulting mixture purified by silica gel with 20% CΗ₃OΗ/EtOAc as an eluent to afford the title compound as a yellow solid.

[0333] ¹H NMR (500 MHz, DMSO-J₆): δ 1.97 (s, 3H), 2.20-2.40 (m, 7H), 3.42 (br s, 6H), 6.85 (br s, IH), 7.19 (d, J = 6.9 Hz, 2H), 7.29 (br s, IH), 7.39 (br s, IH), 7.84 (d, J= 7.4 Hz, 2H), 7.92 (s, IH), 9.19 (s, IH), 11.61 (s, IH)

MS (ES+): m/z 447 (M+H)⁺

Example 109 Preparation of Intermediate

68

4-(4-Methylthiophen-2-yl)-N-(4-((piperazin-l-yl)methyl)phenyl)-7-tosyl-7H- pyrrolo[2,3-rf]pyrimidin-2-amine (68)

[0334] A mixture of l-(bromomethyl)-4-nitrobenzene (2.16 g, 10 mmol), 2-methyl-l- (piperazin-l-yl)propan-l-one (3.9 g, 25 mmol), Na₂CO₃ (2.12 g, 20 mmol) in DMF (50 mL) was heated to 80 ⁰C for 2 h. After cooling to room temperature, the solvent was removed by rotovap. The crude product was dissolved in ethyl acetate (100 mL) and washed by saturated NaHCO₃ (3 x 25 mL). The organic phase was dried over Na₂SO₄ and the salt was removed by filtration. The solvent was removed by rotovap to yield a yellow oil. The above crude oil and 10% Pd/C (50 mg) in ethyl acetate (100 mL) was hydrogenated under a H₂ balloon for 5 h. The Pd/C was removed by filtration and the solvent concentrated by rotovap. The crude product was purified by silica gel column with 10% CH₃OH/CHC1₃ as an eluent to yield l-(4- (4-aminobenzyl)piperazin-l-yl)-2-methylpropan-l-one as a colorless oil (0.6 g, 23% in 2 steps). A mixture of 9 (0.4Og, 1.0 mmol), (0.15 g, 0.64 mmol), l-(4-(4- aminobenzyl)piperazin-l-yl)-2-methylpropan-l-one (0.33 g, 1.25 mmol), Pd(PPh₃)₄ (0.12 g, 0.10 mmol), Na₂CO₃ (0.32 g, 3 mmol) in anhydrous DMF (25 mL) was degassed with argon for 2 min and then heated at 150 ⁰C in a sealed tube for 2 h. After cooling to room temperature, the solvent was removed by rotovap. The crude product was then purified by silica gel column with 20% CH₃OH/CHC1₃ as an eluent to yield a yellow oil (0.1 g, 16%).

Example 110 Preparation of 2-Methyl-l-(4-{4-[4-(4-methyl-thiophen-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino] -benzyl } -piperazin- 1 -yl)-propan- 1 -one

[0335] A mixture of 68 (0.1 g, 0.16 mmol) and Cs₂CO₃ (0.15 g, 0.46 mmol) in CH₃OH (25 niL) was heated to reflux for 5 h. After cooling to room temperature, the solvent was removed by rotovap. The crude product was then purified by silica gel column with 10% CH₃OH/CHC1₃ as an eluent to yield a yellow solid (8 mg, 11%).

[0336] ¹H NMR (500 MHz, DMSO-J₆): δ 0.97 (d, J = 6.6 Hz, 6H), 2.20-2.40 (m, 7H), 2.75-2.90 (m, IH), 3.40-3.50 (m, 6H), 6.84 (d, J = 3.3 Hz, IH), 7.19 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 3.2 Hz, IH), 7.39 (s, IH), 7.84 (d, J = 8.2 Hz, 2H), 7.92 (s, IH), 9.19 (s, IH), 11.62 (br s, IH)

MS (ES+): m/z 475 (M+H)⁺

Example 111 Preparation of Intermediates

69 4-Ethylthiophen-2-yl-2-boronic acid (69)

[0337] To a solution of 3-ethylthiophene (4.2 g, 37.5 mmol) in THF (100 mL) cooled at -78 ⁰C under argon atmosphere was added ra-BuLi (2.5 M in hexanes; 19 mL, 47.5 mmol). The mixture was stirred at the same temperature for 15 min and trimethyllborate added (6.3 mL, 56 mmol). The resulting mixture was stirred at at -78 ⁰C for 15 min and then stirred at RT for 2 h. The reaction was quenched with IM HCl (3 mL) and concentrated. The residue was taken up in water (40 mL) and extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the crude product purified by silica gel column (CHCl₃ to 20% CH₃OH/CHC1₃) to afford the title compound as an off-white solid (2 g, 33%). [0338] ¹H NMR (500 MHz, DMSO-J₆): δ 1.18 (t, J = 7.6 Hz, 3H), 2.59 (q, J = 7.6 Hz, 2H), 7.31 (d, J= 0.8 Hz, IH), 7.50 (d, J= 0.8 Hz, IH), 8.09 (br s, 2H)

70 2-Chloro-4-(4-ethylthiophen-2-yl)-7-tosyl-7H-pyrrolo[2,3-rf]pyrimidine (70)

[0339] A mixture of 8 (0.34 g, 1.0 mmol), 69 (0.20 g, 1.25 mmol), Pd(PPh₃)₄ (0.11 g, 0.1 mmol) and Na₂CO₃ (0.32 g, 3 mmol) in anhydrous DMF (35 mL) was degassed with argon for 2 min and then heated at 150 ⁰C for 5 h. After cooling to room temperature, the solvent was removed by rotovap. The crude product was then purified by silica gel column with 1 : 1 hexanes/CHCl₃ as an eluent to yield a pale yellow solid (0.1 g, 24%).

[0340] ¹H NMR (500 MHz, DMSO-J₆): δ 1.23 (t, J= 7.6 Hz, 3H), 2.37 (s, 3H), 2.67 (q, J = 7.6 Hz, 2H), 7.47 (d, J = 4.2 Hz, IH), 7.50 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 0.7 Hz, 2H), 8.03 (dd, J = SA Hz, 2H), 8.09 (s, IH), 8.10 (s, IH)

71

4-(4-Ethylthiophen-2-yl)-N-(4-(morpholinomethyl)phenyl)-7-tosyl-7H-pyrrolo[2,3- rf]pyrimidin-2-amine hydrochloride (71) [0341] A suspension of 70 (0.1 g, 0.24 mmol), 4-(morpholinomethyl)benzenamine (60 mg, 0.31 mmol), Pd₂(dba)₃ (22 mg, 0.02 mmol), Xantphos (28 mg, 0.05 mmol) and sodium tert- butoxide (70 mg, 0.73 mmol) in anhydrous DMF (25 mL) was degassed with argon for 2 min then heated in a sealed tube at 150 ⁰C for 8 h. After cooling to room temperature, the solvent was removed by rotovap and the resulting mixture purified by silica gel with 20% CH₃OH/CHCI₃ as an eluent to afford the title compound as a yellow solid (50 mg, 36%).

[0342] ¹H NMR (500 MHz, CDCl₃): δ 1.33 (t, J = 7.5 Hz, 3H), 2.43 (s, 3H), 2.78 (q, J = 7.5 Hz, 2H), 2.80-2.30 (m, 2H), 3.38 (d, J = 11.2 Hz, 2H), 3.98 (d, J = 11.3 Hz, 2H), 4.22 (br s, 2H), 4.35 (t, J= 12.1 Hz, 2H), 7.01 (d, J = 4.2 Hz, 1H),7.42 (d, J = 8.0 Hz, 2H), 7.52 (s, IH), 7.72 (d, J = 4.3 Hz, 2H), 7.79 (d, / = 8.1 Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H), 8.90 (s, IH), 11.73 (s, IH), 13.40 (br s, IH)

Example 112 Preparation of 4-(4-Ethylthiophen-2-yl)-N-(4-(morpholinomethyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine

[0343] A mixture of 71 (50 mg, 0.09 mmol) and Cs₂CO₃ (0.15 g, 0.46 mmol) in methanol (10 mL) was refluxed for 5 h. After cooling to room temperature, the solvent was removed by rotovap and the resulting mixture purified by silica gel with 5% CΗ₃OΗ/EtOAc as an eluent to afford the title compound as a yellow solid.

[0344] ¹H NMR (500 MHz, CDCl₃): δ 1.32 (t, J= 7.5 Hz, 3H), 2.40-2.50 (m, 4H), 2.73 (q, J = 1.5 Hz, 2H), 3.45 (s, 2H), 3.72 (t, J = 4.6 Hz, 4H), 6.70-6.80 (m. IH), 6.90-7.00 (m, IH), 7.08 (s, IH), 7.16 (s, IH), 7.29 (d, J = SA Hz, 2H), 7.67 (d, J = SA Hz, 2H), 7.79 (s, IH), 8.74 (br s, IH)

MS (ES+): m/z 420 (M+H)⁺ Example 113 Preparation of Intermediate

72 2-Chloro-4-(4-propylthiophen-2-yl)-7-tosyl-7H-pyrrolo[2,3-rf]pyrimidine (72)

[0345] To a solution of 3-propylthiophene (1.3 g, 10 mmol) in anhydroud THF (25 rnL) cooled at -78 ⁰C under argon atmosphere was added ra-BuLi (2.5 M in hexanes; 4.4 mL, 11 mmol). The mixture was stirred at the same temperature for 15 min and trimethyllborate added (2.2 mL, 20 mmol). The resulting mixture was stirred at at -78 ⁰C for 15 min and then stirred at RT for 2 h. The reaction was quenched with IM HCl (3 mL) and concentrated. The residue was taken up in water (40 mL) and extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the crude product purified by silica gel column (CHCl₃ to 10% CH₃OH/CHCI₃) to afford 4-propylthiophen-2-yl-2-boronic acid as an off-white solid (0.5 g, 29%). A mixture of 8 (0.28 g, 0.82 mmol), 4-propylthiophen-2-yl-2-boronic acid (0.17 g, 1.0 mmol), Pd(PPh₃)₄ (96 mg, 0.08 mmol) and Na₂CO₃ (0.32 g, 3 mmol) in anhydrous DMF (10 mL) was degassed with argon for 2 min and then heated at 120 ⁰C in a sealed tube for 2 h. After cooling to room temperature, the solvent was removed by rotovap. The crude product was then purified by silica gel column with 1 : 1 hexanes/CHCl₃ as an eluent to yield a yellow solid (90 mg, 25%).

[0346] ¹H NMR (500 MHz, CDCl₃): δ 0.96 (t, J = 7.4 Hz, 3H), 1.60-1.75 (m, 2H), 2.42 (s, 3H), 2.63 (t, J = 1.6 Hz, 2H), 6.95 (d, J = 4.0 Hz, IH), 7.22 (s, IH), 7.74 (d, J = 4.2 Hz, IH), 7.79 (s, IH), 8.13 (d, J = 8.4 Hz, 2H)

Example 114 Preparation of N-(4-(Morpholinomethyl)phenyl)-4-(4-propylthiophen-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine

[0347] A suspension of 72 (90 mg, 0.21 mmol), 4-(moφholinomethyl)benzenamine (50 mg, 0.26 mmol), Pd₂(dba)₃ (25 mg, 0.03 mmol), P(t-Bu)₃ (2.0M in toluene, 0.2 mL, 0.4 mmol) and cesium carbonate (0.2 g, 0.61 mmol) in anhydrous DMF (10 mL) was degassed with argon for 2 min then heated in a sealed tube at 150 ⁰C for 3 h. After cooling to room temperature, the solvent was removed by rotovap and the resulting mixture was purified by silica gel with 20% CH₃OH/CHCI₃ as an eluent to afford a yellow solid. A mixture of the above solid and Cs₂CO₃ (0.44 g, 1.35 mmol) in methanol (20 mL) was refluxed for 3 h. After cooling to room temperature, the solvent was removed by rotovap and the crude product purified by silica gel with 10% CH₃OH/CHCI₃ as an eluent to afford the title compound as a yellow solid (10 mg 11% in 2 steps).

[0348] ¹H NMR (500 MHz, CDCl₃): δ 1.00 (t, J = 7.3 Hz, 3H), 1.65-1.80 (m, 2H), 2.40- 2.50 (m, 4H), 2.67 (t, J = 7.5 Hz, 2H), 3.45 (s, 2H), 3.65-3.75 (m, 4H), 6.76 (br s, IH), 7.01 (br s, IH), 7.06 (br s, IH), 7.15 (s, IH), 7.29 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 8.2 Hz, 2H), 7.77 (s, IH), 8.59 (br s, IH)

MS (ES+): m/z 434 (M+H)⁺

Example 115 Preparation of Intermediates

73

4-Chloro-N-(3-(4-methylpiperazin-l-yl)phenyl)-7-tosyl-7H-pyrrolo[2,3- rf]pyrimidin-2-amine (73) [0349] To a solution of 47 (1.70 g, 5 mmol) andp-toluenesulfonyl chloride (1.05 g, 5.5 mmol) in anhydrous CH₂Cl₂ (100 niL) at room temperature under argon atmosphere was added DMAP (0.73 g, 6 mmol). The mixture was stirred at the same temperature for overnight. The solvent was removed by rotovap and the resulting mixture purified by silica gel with 10% CH₃OH/CHCI₃ as an eluent to afford the title compound as a white solid.

[0350] ¹H NMR (500 MHz, CDCl₃): δ 2.34 (s, 6H), 2.59 (t, J = 5.0 Hz, 4H), 3.36 (t, J = 4.9 Hz, 4H), 6.51 (d, J = 4.1 Hz, IH), 6.68 (q, J = 4.5 Hz, IH), 6.68 (q, J = 4.5 Hz, IH), 6.88 (q, J = 3.2 Hz, IH), 7.18 (d, J = 8.2 Hz, 2H), 7.22 (s, IH), 7.25-7.30 (m, IH), 7.43 (d, J = 4.0 Hz, IH), 7.83 (s, IH), 8.01 (d, J = 8.5 Hz, 2H)

74 4-(Morpholinomethyl)thiophen-2-yl-2-boronic acid (74)

[0351] A mixture of 3-methylthiophene (1.96 g, 20 mmol), NBS (4.27 g, 24 mmol) and benzoyl peroxide (50 mg) in CCU (150 mL) was refluxed for 3 h. After cooling to room temperature, the precipitate was removed by filtration and the solvent removed by rotovap to yield 3-(bromomethyl)thiophene as a yellow oil (2.5 g, 71%). The crude product was used for the next reaction without further purification. A mixture of 3-(bromomethyl)thiophene (1.77 g, 10 mmol) and morpholine (1.74 mL, 20 mmol) in THF (25 mL) was refluxed 2 h. After cooling to room temperature, the solvent was removed by rotovap and the resulting mixture purified by silica gel with 10% CH3OH/CHCI3 as an eluent to yield 4-((thiophen-3- yl)methyl)morpholine as a brown oil (1.0 g, 55%). The crude product was used for the next reaction without further purification. To a solution of 4-((thiophen-3-yl)methyl)morpholine (0.5 g, 2.73 mmol) in THF (20 mL) cooled at -78 ⁰C under argon atmosphere was added n- BuLi (2.5 M in hexanes; 1.2 mL, 3.0 mmol). The mixture was stirred at the same temperature for 15 min and trimethyllborate added (6.3 mL, 56 mmol). The resulting mixture was stirred at at -78 ⁰C for 15 min and then stirred at RT for 2 h. The reaction was quenched with IM HCl (3 mL) and concentrated. The residue was taken up in water (40 mL) and extracted with EtOAc (2 x 40 niL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the crude product purified by silica gel column (CHCl₃ to 20% CH₃OH/CHCI₃) to yield the title compound as an off- white solid (0.14 g, 23%). The crude product was used for the next reaction without further purification.

Example 116 Preparation of N-(3-(4-Methylpiperazin-l-yl)phenyl)-4-(4- (morpholinomethyl)thiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine

[0352] A mixture of 73 (0.18 g, 0.35 mmol), 74 (0.10 g, 0.44 mmol), Pd(PPh₃)₄ (42 mg, 0.04 mmol) and Cs₂CO₃ (0.34 g, 1.0 mmol) in anhydrous dioxane (25 mL) was degassed with argon for 2 min and then was heated to reflux under argon for 3 h. After cooling to room temperature, the solvent was removed by rotovap. The crude product was then purified by silica gel column with 1:1 hexanes/CΗCl₃ as an eluent to yield a yellow oil (0.1 g, 44%). A mixture of the above oil (0.1 g, 0.16 mmol) and Cs₂CO₃ (0.15 g, 0.46 mmol) in dioxane (10 mL) and DMF (5 mL) was refluxed for 3 h. After cooling to room temperature, the solvent was removed by rotovap and the resulting mixture purified by silica gel with 30% CH₃OH/CHC1₃ as an eluent to afford the title compound as a yellow solid (4 mg, 5%).

[0353] ¹H NMR (500 MHz, DMSO-J₆): δ 2.22 (s, 3H), 2.40 (br s, 4H), 3.16 (br s, 4H), 3.55 (s, 2H), 3.60 (br s, 4H), 6.48 (q, J = 4.5 Hz, IH), 6.78 (q, J = 2.8 Hz, IH), 7.09 (t, J = 8.1 Hz, IH), 7.30-7.40 (m, 2H), 7.55-7.65 (m, 2H), 7.95 (s, IH), 9.03 (s, IH), 11.63 (br s, IH)

MS (ES+): m/z 490 (M+H)⁺ Example 117 Preparation of Intermediates

75 5-Cyanobenzo[^]thiophen-2-yl-2-boronic acid (75)

[0354] To a solution of benzo[b]thiophene-5-carbonitrile (0.33 g, 2.1 mmol) in anhydrous THF (12 rnL) cooled at -78 ⁰C under argon atmosphere was added ra-BuLi (1.7 M in pentane, 1.5 mL, 2.5 mmol). The mixture was stirred at the same temperature for 15 min and trimethyllborate added (6.3 mL, 56 mmol). The resulting mixture was stirred at at -78 ⁰C for 15 min and then stirred at RT for 2 h. The reaction was quenched with IM HCl (3 mL) and concentrated. The residue was taken up in water (40 mL) and extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the crude product purified by silica gel column (CHCl₃ to 20% CH₃OH/CHCI₃) to afford the title compound as an off-white solid (0.2 g, 47%).

[0355] ¹H NMR (500 MHz, DMSO-J₆): δ 7.65-7.75 (m, IH), 8.07 (s, IH), 8.21 (d, J = 8.4 Hz, IH), 8.50 (s, 1), 8.69 (br s, 2H)

76

4-Chloro-N-(4-(4-methylpiperazin-l-yl)phenyl)-7-tosyl-7H-pyrrolo[2,3- rf]pyrimidin-2-amine (76)

[0356] To a solution of 20 (1.70 g, 5 mmol) andp-toluenesulfonyl chloride (1.05 g, 5.5 mmol) in anhydrous CH₂Cl₂ (80 mL) and THF (30 mL) at room temperature under argon atmosphere was added DMAP (0.73 g, 6 mmol). The mixture was stirred at the same temperature for overnight. The solvent was removed by rotovap and the resulting mixture purified by silica gel with 10% CH₃OH/CHCI₃ as an eluent to afford the title compound as a pale yellow solid (1.2 g, 48%). Example 118 Preparation of 2-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)benzo[b]thiophene-5-carbonitrile

[0357] A mixture of 76 (0.14g, 0.29 mmol), 75 (71 mg, 0.35 mmol), Pd(PPh₃)₄ (0.12 g, 0.10 mmol), CS₂CO₃ (0.32 g, 3 mmol) in anhydrous dioxane (20 mL) was degassed with argon for 2 min and then heated to reflux for 8 h. After cooling to room temperature, the solvent was removed by rotovap. The crude product was then purified by silica gel column with 20% CΗ₃OΗ/CΗC1₃ as an eluent to yield a yellow solid. A mixture of the above yellow solid and Cs₂CO₃ (0.15 g, 0.46 mmol) in dioxane (25 mL) was heated to reflux for 3 h. After cooling to room temperature, the solvent was removed by rotovap. The crude product was then purified by silica gel column with 10% CH₃OH/CHC1₃ as an eluent to yield a yellow solid (40 mg, 30% in 2 steps).

[0358] ¹H NMR (500 MHz, CDCl₃): δ 2.38 (br s, 3H), 2.67 (br s, 4H), 3.16 (br s, 4H), 6.90-7.00 (m, 3H), 7.35-7.45 (m, IH), 7.74 (d, J = 8.9 Hz, 2H), 7.81 (q, J = 3.3 Hz, IH), 8.31 (d, J = 8.4 Hz, IH), 8.48 (s, IH), 8.55 (s, IH), 9.12 (s, IH), 11.72 (s, IH)

MS (ES+): m/z 466 (M+H)⁺

Example 119 Preparation of Intermediate

77 4-((Diethylamino)methyl)thiophen-2-yl-2-boronic acid (77) [0359] A mixture of 3-(bromomethyl)thiophene (1.77 g, 10 mmol) and diethylamine (2.06 niL, 20 mmol) in THF (25 mL) was refluxed 2 h. After cooling to room temperature, the solvent was removed by rotovap and the resulting mixture purified by silica gel with 10% CH₃OH/CHCI₃ as an eluent to yield N-ethyl-N-((thiophen-3-yl)methyl)ethanamine as a brown oil (1.0 g, 30%). The crude product was used for the next reaction without further purification. To a solution of N-ethyl-N-((thiophen-3-yl)methyl)ethanamine (0.85 g, 5.0 mmol) in THF (25 mL) cooled at -78 ⁰C under argon atmosphere was added t-Buhi (1.7 M in pentane; 3.2 mL, 5.5 mmol). The mixture was stirred at the same temperature for 15 min and trimethyllborate added (1.1 mL, 10 mmol). The resulting mixture was stirred at -78 ⁰C for 15 min and then stirred at RT for 2 h. The reaction was quenched with IM HCl (3 mL) and concentrated. The residue was taken up in water (40 mL) and extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the crude product purified by silica gel column (CHCI₃ to 20% CH₃OH/CHCI₃) to yield 4-((diethylamino)methyl)thiophen-2-yl-2-boronic acid as an off-white solid (160 mg, 15%). The crude product was used for the next reaction without further purification.

Example 120 Preparation of 4-(4-((Diethylamino)methyl)thiophen-2-yl)-N-(4-(4- methylpiperazin-l-yl)phenyl)-7H-pyrrolo[2,3-(i]pyrimidin-2-amine

[0360] A mixture of 76 (93 mg, 0.19 mmol), 77 (50 mg, 0.23 mmol), Pd(PPh₃)₄ (42 mg, 0.04 mmol) and CS₂CO₃ (0.18 g, 0.55 mmol) in anhydrous DMF (25 mL) was degassed with argon for 2 min and then was heated to reflux under argon for 3 h. After cooling to room temperature, the solvent was removed by rotovap. The crude product was then purified by silica gel column with 35% CΗ₃OΗ/CΗCI₃ as an eluent to yield yellow solid. A mixture of the above yellow solid and CS₂CO₃ (0.15 g, 0.46 mmol) in dioxane (25 mL) was heated to reflux for 3 h. After cooling to room temperature, the solvent was removed by rotovap. The crude product was then purified by silica gel column with 10% CH₃OH/CHCI₃ as an eluent to yield a yellow solid (10 mg, 11% in 2 steps).

[0361] ¹H NMR (500 MHz, CDCl₃): δ 1.00-1.20 (m, 8H), 2.36 (s, 3H), 2.50-2.70 (m, 6H), 3.18 (t, J= 4.7 Hz, 2H), 3.66 (s, 2H), 6.70-6.80 (m, IH), 6.90 (s, IH), 6.92-7.00 (m, 3H), 7.30 (s, IH), 7.58 (d, J = 8.0 Hz, 2H), 7.86 (s, IH), 8.66 (br s, IH)

MS (ES+): m/z 466 (M+H)⁺

Example 121 Preparation of Intermediates

78 5-{2-Chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-rf]pyrimidin-4-yl}-3- methylthiophene-2-carbaldehyde (78)

[0362] To a 20 mL of microwave vial was charged with methyl 8 (1.47 g, 4.29 mmol), 5- formyl-4-methylthiophene-2-boronic acid 1,3-propanediol cyclic ester (0.95 g, 4.52 mmol), dichloro[l,l'-bis(di-fert-butylphosphino)ferrocene]palladium(II) (Pd-118) (280 mg, 0.429 mmol), solid K₂CO₃ (1.18 g, 8.58 mmol) and anhydrous DMF (20 mL). The reaction mixture was purged with argon gas for 5 min, and then the vial was sealed and irradiated in a microwave (Initiator, Biotage) at 110 ⁰C for 90 min. After cooling to room temperature, the formed dark-red solution was diluted with EtOAc (200 mL), washed with water (3 x 50 mL), brine (2 x 50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo with ca. 15 g of silica gel. The loaded silica gel was taken to the ISCO system for purification using 20 to 100% EtOAc gradient in hexanes. Fractions, containing the product, were concentrated in vacuo to give a dark- yellow solid. It was re-crystallized from 10 mL of EtOAc to give the title product as a yellow solid (2.02 g, 54% yield). [0363] ¹H NMR (500 MHz, DMSO-J₆): δ 2.34 (s, 3H), 2.61 (s, 3H), 7.48-7.50 (m, 3H), 8.04 (d, J = 8.4 Hz, 2H), 8.16 (s, IH), 8.19 (d, J = 4.1 Hz, IH), 10.09 (s, IH)

MS (ES+): m/z 432 (M+H)⁴

79

5-(2-{[4-(lH-Imidazol-l-yl)phenyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H- pyrrolo[2,3-rf]pyrimidin-4-yl)-3-methylthiophene-2-carbaldehyde (79)

[0364] To a 5 niL of microwave vial was charged with 78 (216 mg, 0.5 mmol), 4-(1H- imidazol-l-yl)aniline (160 mg, 1.0 mmol), Pd(OAc)₂ (22.5 mg, 0.1 mmol), anhydrous DMF (4 mL), Et₃N (0.7 mL, 5.0 mmol) and 1.0 M solution of P(J-Bu)₃ (0.2 mL, 0.2 mmol). The reaction mixture was purged with argon gas for 5 min, and then the vial was sealed and irradiated in a microwave (Initiator, Biotage) at 160 ⁰C for 30 min. After cooling to room temperature, the reaction mixture was filtered through 0.2 u syringe filter and purified by reverse-phase preparative ΗPLC in CΗ₃CN/Η₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and partitioned between EtOAc (100 mL) and saturated aqueous NaHCO₃ (50 mL). The organic layer was washed with brine (1 x 30 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title product as a bright-orange solid (110 mg, 40% yield).

Example 122 Preparation of [5-(2-{ [4-(lH-Imidazol-l-yl)phenyl]amino}-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylthiophen-2-yl]methanol

[0365] To a solution of 79 (110 mg, 0.198 mmol) in 20 niL of anhydrous THF was added solid LiAlH₄ (75 mg, 1.98 mmol) in small portions. The reaction mixture was stirred at ambient temperature for 30 min. Upon the completion of the reaction as judged by LC/MS, 2 mL of EtOAc was added to quench the reaction, and the mixture was stirred for an additional 30 min. Then the reaction mixture was diluted with 20 mL of MeOH and solid K₂CO₃ was added. The mixture was left to stir at ambient temperature overnight. Then it was partitioned between EtOAc and water. EtOAc layer was washed with brine (2 x 50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was dissolved in 2 mL of DMF and purified by reverse-phase preparative HPLC in CH₃CN/H₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and partitioned between EtOAc (50 mL) and saturated aqueous NaHCO₃ (50 mL). The organic layer was washed with brine (2 x 30 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title product as a yellow solid (24 mg, 30% yield).

[0366] ¹H NMR (500 MHz, DMSO-J₆): δ 2.23 (s, 3H), 4.65 (d, J = 5.5 Hz, 2H), 5.53 (t, J = 5.5 Hz, IH), 6.86 (dd, J = 3.6, 1.8 Hz, IH), 7.08 (s, IH), 7.30 (dd, J = 3.5, 2.3 Hz, IH), 7.54 (d, J = 9.0 Hz, 2H), 7.68 (s, IH), 7.84 (s, IH), 8.04 (d, J = 9.0 Hz, 2H), 8.17 (s, IH), 9.40 (s, IH), 11.67 (s, IH)

MS (ES+): m/z 403 (M+H)⁺

Example 123 Preparation of [5-(2-{ [4-(lH-imidazol-l-yl)phenyl]amino}-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylthiophen-2-yl]methyl acetate

[0367] The title product was isolated as a by-product of the following reaction. To a solution of 79 (110 mg, 0.198 mmol) in 20 rnL of anhydrous THF was added solid LiAlH₄ (75 mg, 1.98 mmol) in small portions. The reaction mixture was stirred at ambient temperature for 30 min. Upon the completion of the reaction as judged by LC/MS, 2 mL of EtOAc was added to quench the reaction and the mixture was stirred for an additional 30 min. Then the reaction mixture was diluted with 20 mL of MeOH and solid K₂CO₃ was added. The mixture was left to stir at ambient temperature overnight. Then it was partitioned between EtOAc and water. EtOAc layer was washed with brine (2 x 50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was dissolved in2 mL of DMF and purified by reverse- phase preparative HPLC in CH₃CN/H₂O system containing 0.1% of TFA. Two products were isolated, [5-(2-{ [4-(lH-Imidazol-l-yl)phenyl]amino}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylthiophen-2-yl] methanol and [5-(2-{ [4-( IH- imidazol-1-yl )phenyl] amino} -7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylthiophen-2-yl]methyl acetate. Fractions, containing the latter product, were combined and partitioned between EtOAc (50 mL) and saturated aqueous NaHCO₃ (50 mL). The organic layer was washed with brine (2 x 30 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title product as a yellow solid (16 mg, 18% yield).

[0368] ¹H NMR (500 MHz, DMSO-J₆): δ 2.07 (s, 3H), 2.31 (s, 3H), 5.25 (s, 2H), 6.88 (dd, /= 3.6, 1.6 Hz, IH), 7.08 (s, IH), 7.33 (dd, J = 3.5, 2.3 Hz, IH), 7.54 (d, J = 9.0 Hz, 2H), 7.67 (s, IH), 7.88 (s, IH), 8.03 (d, J = 9.0 Hz, 2H), 8.17 (s, IH), 9.44 (s, IH), 11.72 (s, IH)

MS (ES+): m/z 445 (M+H)⁺ Example 124 Preparation of Intermediate

80

3-Methyl-5-(7-[(4-methylphenyl)sulfonyl]-2-{[4-(2-pyrrolidin-l- ylethoxy)phenyl]amino}-7H-pyrrolo[2,3-rf]pyrimidin-4-yl)thiophene-2- carbadehyde (80)

[0369] To a 5 rnL of microwave vial was charged with 78 (216 mg, 0.5 mmol), 4- (2- pyrrolidin-l-ylethoxy)-aniline (222 mg, 1.0 mmol), Pd(OAc)₂ (22.5 mg, 0.1 mmol), anhydrous DMF (4 mL), Et₃N (0.7 mL, 5.0 mmol) and 1.0 M solution of P(^-Bu)₃ (0.2 mL, 0.2 mmol). The reaction mixture was purged with argon gas for 5 min, and then the vial was sealed and irradiated in a microwave (Initiator, Biotage) at 160 ⁰C for 30 min. After cooling to room temperature, the reaction mixture was filtered through 0.2 u syringe filter and purified by reverse-phase preparative HPLC in CH₃CN/H₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and partitioned between EtOAc (100 mL) and saturated aqueous NaHCO₃ (50 mL). The organic layer was washed with brine (2 x 30 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title product as a bright-orange solid (143 mg, 47% yield).

Example 125 Preparation of [3-Methyl-5-(2-{ [4-(2-pyrrolidin- l-ylethoxy)phenyl] amino} -7H- pyrrolo[2,3-d]pyrimidin-4-yl)thiophen-2-yl]methanol

[0370] To a solution of 80 (143 mg, 0.237 mmol) in 20 niL of anhydrous THF was added solid LiAlH₄ (180 mg, 2.72 mmol) in small portions. The reaction mixture was stirred at ambient temperature for 30 min. Upon the completion of the reaction as judged by LC/MS, 2 mL of saturated aqueous NaHCO₃ were added to quench the reaction and the mixture was stirred for an additional 30 min. Then the reaction mixture was diluted with 20 mL of MeOH and solid K₂CO₃ (1 g) was added. The mixture was left to stir at ambient temperature overnight. Then it was partitioned between EtOAc and water. EtOAc layer was washed with brine (2 x 50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was dissolved in2 mL of DMF and purified by reverse-phase preparative HPLC in CH₃CN/H₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and partitioned between EtOAc (50 mL) and saturated aqueous NaHCO₃ (50 mL). The organic layer was washed with brine (2 x 30 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title product as a bright- yellow solid (74 mg, 69% yield).

[0371] ¹H NMR (500 MHz, DMSO-J₆): δ 1.67-1.71 (m, 4H), 2.22 (s, 3H), 2.58 (br s, 4H), 2.83 (br s, 2H), 4.05 (t, J = 5.9 Hz, 2H), 4.64 (d, J = 4.7 Hz, 2H), 5.51 (t, J = 5.4 Hz, IH), 6.80 (dd, J = 3.5, 1.6 Hz, IH), 6.87 (d, J= 9.0 Hz, 2H), 7.22 (dd, J= 3.1, 1.3 Hz, IH), 7.77 (d, J = 9.0 Hz, 2H), 7.79 (s, IH), 8.96 (s, IH), 11.53 (s, IH)

MS (ES+): m/z 450 (M+H)⁺

Example 126 Preparation of Intermediate

81

5-[2-({4-[(2-Methyl-lH-imidazol-l-yl)methyl]phenyl]amino}-7H-pyrrolo[2,3- rf]pyrimidin-4-yl)-3-methylthiophene-2-carbaldehyde (81) [0372] To a 20 niL of microwave vial was charged with 78 (432 mg, 1.0 mmol), (2-methyl- lH-imidazol-l-yl)methyl-aniline (375 mg, 2.0 mmol), Pd₂(dba)₃ (92 mg, 0.1 mmol), XantPhos (116 mg, 0.2 mmol), solid Cs₂CO₃ (652 mg, 2.0 mmol) and anhydrous dioxane (20 mL). The reaction mixture was purged with argon gas for 5 min, and then the vial was sealed and irradiated in a microwave (Initiator, Biotage) at 160 ⁰C for 30 min. After cooling to room temperature, the formed dark-red solution was diluted with EtOAc (200 mL), washed with water (3 x 50 mL), brine (2 x 50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo with ca. 15 g of silica gel. The loaded silica gel was taken to the ISCO system for purification using 0 to 10% MeOH gradient in DCM. Fractions, containing the product, were concentrated in vacuo to give the title product as a yellow solid (200 mg, 34% yield).

Example 127 Preparation of {3-Methyl-5-[2-({4-[(2-methyl-lH-imidazol-l- yl)methyl]phenyl]amino}-7H-pyrrolo[2,3-(i]pyrimidin-4-yl)thiophen-2-yl}methanol

[0373] To a solution of 81 (200 mg, 0.343 mmol) in 20 mL of anhydrous TΗF was added solid NaBH₄ (65 mg, 1.72 mmol) in small portions. The reaction mixture was stirred at ambient temperature for 2 h. Upon the completion of the reaction as judged by LC/MS, the reaction mixture was diluted with 20 mL of MeOH and solid Cs₂CO₃ (326 mg) was added. The reaction mixture was brought to reflux and refluxed for 30 min. Then it was partitioned between EtOAc and water. EtOAc layer was washed with brine (2 x 50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using 0 to 20% MeOH gradient in DCM. Fractions, containing the product, were combined and concentrated in vacuo to give the title product as a light-yellow solid (112 mg, 76% yield).

[0374] ¹H NMR (500 MHz, DMSO-J₆): δ 2.22 (s, 3H), 2.26 (s, 3H), 4.64 (d, J = 4.3 Hz, 2H), 5.05 (s, 2H), 5.52 (t, J = 5.2 Hz, IH), 6.75 (d, J = 0.7 Hz, IH), 6.83 (dd, J= 3.7, 1.8 Hz, IH), 7.10 (d, J = 8.6 Hz, 2H), 7.12 (d, J = 1.0 Hz, IH), 7.28 (dd, J = 3.5, 2.4 Hz, IH), 7.81 (s, IH), 7.88 (d, J = 8.7 Hz, 2H), 9.23 (s, IH), 11.59 (s, IH)

MS (ES+): m/z 431 (M+H)⁺

Example 128 Preparation of Intermediates

82 før/-Butyl 6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (82)

[0375] To a suspension of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride salt (5 g, 28.46 mmol) in 150 mL Of CH₂Cl₂ was added Et₃N (3.17 g, 31.30 mmol), followed by solid di-tert-butyl dicarbonate (6.83 g, 31.30 mmol). The reaction mixture was stirred at ambient temperature for 2 h. Then it washed it water (2 x 100 mL), brine (2 x 100 mL), dried over anhydrous Na₂SO₄ and filtered. Solvent was removed in vacuo to give colourless oil (6.8 g, 100% yield), which solidified into a white solid.

83

[5-(/er/-Butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl]boronic acid

(83)

[0376] To a solution of 82 (1.2 g, 5.0 mmol) and triisopropyl borate (1.41 g, 7.5 mmol) in 50 mL of anhydrous THF at -10 ⁰C under argon atmosphere was added 1.5 M solution of LDA in THF (5.0 mL, 7.5 mmol) dropwise via a syringe. The reaction mixture was left to slowly warm up to ambient temperature over 3 h and left to stir at ambient temperature overnight. Then it was quenched with 50 mL of IN HCl. The resulting solution was stirred for 20 min, and then extracted with EtOAc (4 x 50 niL). The combined EtOAc extracts were washed with brine (3 x 50 rnL), dried over anhydrous Na₂SO₄ and concentrated in vacuo with ca. 15 g of silica gel. The loaded silica gel was taken to the ISCO system for further purification (80 g column, solid method, 10 to 100% EtOAc gradient in hexanes, followed by 20% MeOH in EtOAc). Fractions, containing the product, were combined and concentrated in vacuo to give the title compound as yellow oil (0.75 g, 53% yield), which was re-crystallized into a white solid.

84 ^r/-Butyl 2-(2-{[4-(4-methylpiperazin-l-yl)phenyl]amino}-7H-pyrrolo[2,3- rf]pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (84)

[0377] To a 5 mL of microwave vial was charged with 20 (254 mg, 0.742 mmol), Pd(PPh₃ )₄ (86 mg, 0.0742 mmol), 83 (210 mg, 0.742 mmol), solid K₂CO₃ (205 mg, 1.48 mmol) and with 5 mL of anhydrous DMF. The mixture was purged with argon gas for 10 min, then sealed and irradiated in a microwave (Initiator, Biotage) at 160 ⁰C for 40 min. The resulting reaction mixture was filtered through 0.2 u syringe filter and purified by reverse- phase preparative HPLC in CH₃CN/H₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (100 mL). The solution was treated with saturated aqueous NaHCO₃ (2 x 30 mL), washed with brine (2 x 30 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a bright-yellow solid (195 mg, 48% yield).

Example 129 Preparation of N-[4-(4-Methylpiperazin-l-yl)phenyl]-4-(4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-yl)-7H-pyrrolo[2,3-(i]pyrimidin-2-amine

[0378] Compound 84 (195 mg, 0.357 mmol) was treated with 20 niL of 50% TFA in CH₂Cl₂ for 10 min. The resulting solution was concentrated down in vacuo. The residue was re-dissolved in 3 rnL of DMF, filtered through 0.2 u syringe filter and purified by reverse- phase preparative HPLC in CH₃CNZH₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (100 mL). The solution was treated with saturated aqueous NaHCO₃ (2 x 30 mL), washed with brine (2 x 30 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (120 mg, 75% yield).

[0379] ¹H NMR (500 MHz, DMSO-J₆): δ 2.22 (s, 3H), 2.46 (t, J = 4.9 Hz, 4H), 2.80 (t, J = 5.3 Hz, 2H), 3.04-3.06 (m, 6H), 3.87 (s, 2H), 6.78 (dd, J = 3.6, 1.6 Hz, IH), 6.88 (d, J = 9.1 Hz, 2H), 7.21 (dd, J = 3.5, 2.2 Hz, IH), 7.71 (d, J = 9.0 Hz, 2H), 7.76 (s, IH), 8.87 (s, IH), 11.50 (s, IH)

MS (ES+): m/z 446 (M+H)⁺

Example 130 Preparation of Λ^4-(4-Methylpiperazin-l-yl)phenyl]-4-[5-(methylsulfonyl)- 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl]-7H-pyrrolo[2,3-d]pyrimidin-2-amm^

[0380] To a solution of N-[4-(4-Methylpiperazin-l-yl)phenyl]-4-(4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-yl)-7H-pyrrolo[2,3-(i]pyrimidin-2-amine (12 mg, 0.027 mmol) in 2 niL of anhydrous DMF was added one drop of Et₃N, followed by 0.3 rnL of a solution of methanesulfonyl chloride (3.1 mg, 0.027 mmol) in anhydrous dioxane (10 mg in 1 mL). The reaction mixture was stirred at ambient temperature for 30 min, then filtered through 0.2 u syringe filter and purified by reverse-phase preparative ΗPLC in CΗ₃CN/Η₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (30 mL). The solution was treated with saturated aqueous NaHCO₃ (2 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (6 mg, 43% yield).

[0381] ¹H NMR (500 MHz, DMSO-J₆): δ 2.24 (s, 3H), 2.49-2.50 (m, 4H), 2.98 (s, 3H), 3.02 (t, J = 5.5 Hz, 2H), 3.05-3.07 (m, 4H), 3.54 (t, J = 5.7 Hz, 2H), 4.39 (s, 2H), 6.80 (dd, J = 3.6, 1.7 Hz, IH), 6.89 (d, J = 9. I Hz, 2H), 7.24 (dd, J = 3.4, 2.4 Hz, IH), 7.71 (d, J = 9.1 Hz, 2H), 7.88 (s, IH), 8.91 (s, IH), 11.54 (s, IH)

MS (ES+): m/z 524 (M+H)⁺

Example 131 Preparation of 4-(5-Acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)- N-[A-(A- methylpiperazin-l-yl)phenyl]-7H-pyrrolo[2,3-(i]pyrimidin-2-amine

[0382] To a solution of N-[4-(4-Methylpiperazin-l-yl)phenyl]-4-(4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-yl)-7H-pyrrolo[2,3-(i]pyrimidin-2-amine (30 mg, 0.067 mmol) in 2 mL of anhydrous DMF was added one drop of Et₃N, followed by 0.4 mL of a solution of acetyl chloride (5.3 mg, 0.067 mmol) in anhydrous dioxane (13.2 mg in 1 mL). The reaction mixture was stirred at ambient temperature for 30 min, then filtered through 0.2 u syringe filter and purified by reverse-phase preparative HPLC in CH₃CN/H₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (30 mL). The solution was treated with saturated aqueous NaHCO₃ (2 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a bright- yellow solid (17 mg, 52% yield).

[0383] ¹H NMR (500 MHz, DMSO-J₆, 80 ⁰C): δ 2.12 (s, 3H), 2.28 (s, 3H), 2.52 (t, J = 4.9 Hz, 4H), 2.95 (t, J = 5.5 Hz, 2H), 3.11 (t, J = 5.0 Hz, 4H), 3.81 (t, J = 5.5 Hz, 2H), 4.64 (s, 2H), 6.75 (dd, J = 3.5, 1.6 Hz, IH), 6.89 (d, J= 9.1 Hz, 2H), 7.17 (dd, J= 3.4, 2.3 Hz, IH), 7.68 (d, J = 9.1 Hz, 2H), 7.78 (s, IH), 8.41 (s, IH), 11.19 (s, IH)

MS (ES+): m/z 488 (M+H)⁺

Example 132 Preparation of 4-[5-(2,2-Dimethylpropanoyl)-4,5,6,7-tetrahydrothieno[3,2- c]pyridine-2-yl]-N-[4-(4-methylpiperazin-l-yl)phenyl]-7H-pyrrolo[2,3-(i]pyrimidin-2-amine

[0384] To a solution of N-[4-(4-Methylpiperazin-l-yl)phenyl]-4-(4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-yl)-7H-pyrrolo[2,3-(i]pyrimidin-2-amine (60 mg, 0.135 mmol) in 2 mL of anhydrous DMF was added one drop of Et₃N, followed by 0.4 mL of a solution of trimethylacetyl chloride (16.2 mg, 0.135 mmol) in anhydrous dioxane (40.5 mg in 1 mL). The reaction mixture was stirred at ambient temperature for 30 min, then filtered through 0.2 u syringe filter and purified by reverse-phase preparative ΗPLC in CΗ₃CN/Η₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (30 mL). The solution was treated with saturated aqueous NaHCO₃ (2 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a bright- yellow solid (22 mg, 31% yield). [0385] ¹H NMR (500 MHz, DMSO-J₆,): δ 1.25 (s, 9H), 2.30 (s, 3H), 2.57 (br s, 4H), 2.90 (t, J= 5.1 Hz, 2H), 3.09 (br s, 4H), 3.89 (t, J = 5.6 Hz, 2H), 4.69 (s, 2H), 6.83 (dd, J= 3.7, 1.8 Hz, IH), 6.89 (d, J= 9.1 Hz, 2H), 7.24 (dd, J= 3.5, 2.4 Hz, IH), 7.70 (d, J = 9.1 Hz, 2H), 7.92 (s, IH), 8.91 (s, IH), 11.53 (s, IH)

MS (ES+): m/z 530 (M+H)⁺

Example 133 Preparation of Λ/,Λ^Diethyl-2-(2-{ [4-(4-methylpiperazin-l-yl)phenyl] amino }- 7H-pyrrolo[2,3-(i]pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide

[0386] To a solution of N-[4-(4-Methylpiperazin-l-yl)phenyl]-4-(4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-yl)-7H-pyrrolo[2,3-(i]pyrimidin-2-amine (30 mg, 0.067 mmol) in 2 mL of anhydrous DMF was added one drop of Et₃N, followed by 0.4 mL of a solution of diethylcarbamyl chloride (9.12 mg, 0.067 mmol) in anhydrous dioxane (23 mg in 1 mL). The reaction mixture was stirred at ambient temperature for 30 min, then filtered through 0.2 u syringe filter and purified by reverse-phase preparative ΗPLC in CΗ₃CN/Η₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (30 mL). The solution was treated with saturated aqueous NaHCO₃ (2 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a bright- yellow solid (18 mg, 49% yield).

[0387] ¹H NMR (500 MHz, DMSO-J₆,): δ 1.09 (t, J = 7.0 Hz, 6H), 2.23 (s, 3H), 2.47 (br s, 4H), 2.93 (t, J= 5.1 Hz, 2H), 3.06 (t, J= 4.7 Hz, 4H), 3.18 (q, J = 7.1 Hz, 4H), 3.46 (t, J= 5.5 Hz, 2H), 4.30 (s, 2H), 6.82 (dd, / = 3.7, 1.8 Hz, IH), 6.88 (d, / = 9.1 Hz, 2H), 7.23 (dd, / = 3.6, 2.3 Hz, IH), 7.71 (d, /= 9.1 Hz, 2H), 7.86 (s, IH), 8.89 (s, IH), 11.51 (s, IH)

MS (ES+): m/z 545 (M+H)⁺ Example 134 Preparation of N-[4-(4-Methylpiperazin-l-yl)phenyl]-4-[5-(pyridin-3- ylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl]-7H-pyrrolo[2,3-(i]pyrimidin-2-amine

[0388] To a solution of N-[4-(4-Methylpiperazin-l-yl)phenyl]-4-(4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-yl)-7H-pyrrolo[2,3-(i]pyrimidin-2-amine (60 mg, 0.135 mmol) in 2 rnL of anhydrous DMF was added one drop of Et₃N, followed by solid nicotinoyl chloride hydrochloride salt (30 mg, 0.168 mmol). The reaction mixture was stirred at ambient temperature for 30 min, then filtered through 0.2 u syringe filter and purified by reverse-phase preparative ΗPLC in CΗ₃CN/Η₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (30 mL). The solution was treated with saturated aqueous NaHCO₃ (2 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a bright- yellow solid (68 mg, 91% yield).

[0389] ¹H NMR (500 MHz, DMSO-J₆, 60 ⁰C): δ 2.12 (s, 3H), 2.39 (br s, 4H), 2.80 (t, J = 5.3 Hz, 2H), 2.92 (m, 4H), 3.62 (br s, 2H), 4.53 (br s, 2H), 6.57 (br s, IH), 6.69 (d, J = 9.0 Hz, 2H), 6.98 (br s, IH), 7.31 (dd, J = 7.8, 4.9 Hz, IH), 7.50 (d, J = 9.0 Hz, 2H), 7.63 (br s, IH), 7.70-7.71 (m, IH), 8.44 (s, IH), 8.48-8.49 (m, 2H), 11.14 (s, IH)

MS (ES+): m/z 551 (M+H)⁺

Example 135 Preparation of Intermediates

85

/er/-Butyl 2-(2-{[3-(4-methylpiperazin-l-yl)phenyl]amino}-7H-pyrrolo[2,3- rf]pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (85)

[0390] To a 20 niL of microwave vial was charged with 47 (1.03 g, 3.0 mmol), Pd(PPh₃)₄ (347 mg, 0.3 mmol), 83 (0.85 g, 3.0 mmol), solid K₂CO₃ (0.83 g, 6.0 mmol) and with 20 mL of anhydrous DMF. The mixture was purged with argon gas for 10 min, then sealed and irradiated in a microwave (Initiator, Biotage) at 160 ⁰C for 50 min. The resulting reaction mixture was filtered through 0.2 u syringe filter and purified by reverse-phase preparative HPLC in CH₃CN/H₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (100 mL). The solution was treated with saturated aqueous NaHCO₃ (2 x 50 mL), washed with brine (2 x 50 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a bright- yellow solid (0.677 g, 41% yield).

86

N-[3-(4-Methylpiperazin-l-yl)phenyl]-4-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine- 2-yl)-7H-pyrrolo[2,3-rf]pyrimidin-2-amine (86) [0391] Compound 85 (677 mg, 1.24 mmol) was treated with 40 niL of 50% TFA in CH₂Cl₂ for 10 min. The resulting solution was concentrated down in vacuo. The residue was re- dissolved in 5 rnL of MeOH, and this solution diluted with 50 rnL of DCM. The resulting solution was treated with saturated aqueous NaHCO₃ (2 x 30 rnL), washed with brine (2 x 30 rnL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (525 mg, 95% yield).

Example 136 Preparation of Λ^3-(4-Methylpiperazin-l-yl)phenyl]-4-[5-(methylsulfonyl)- 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl]-7H-pyrrolo[2,3-d]pyrimidin-2-amm^

[0392] To a solution of 86 (60 mg, 0.135 mmol) in 2 mL of anhydrous DMF was added one drop of Et₃N, followed by 0.5 mL of a solution of methanesulfonyl chloride (15.4 mg, 0.135 mmol) in anhydrous dioxane (31 mg in 1 mL). The reaction mixture was stirred at ambient temperature for 30 min, then filtered through 0.2 u syringe filter and purified by reverse-phase preparative ΗPLC in CΗ₃CN/Η₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (30 mL). The solution was treated with saturated aqueous NaHCO₃ (2 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (41 mg, 58% yield).

[0393] ¹H NMR (500 MHz, DMSO-J₆): δ 2.53 (br s, 3H), 2.90 (br s, 4H), 2.99 (s, 3H), 3.03 (t, J = 5.4 Hz, 2H), 3.32 (br s, 4H), 3.55 (t, J = 5.7 Hz, 2H), 4.40 (s, 2H), 6.51 (dd, J = 8.1, 1.9 Hz, IH), 6.84 (dd, J = 3.7, 1.7 Hz, IH), 7.12 (t, J = 8.1 Hz, IH), 7.29-7.32 (m, 2H), 7.72 (s, IH), 7.91 (s, IH), 9.06 (s, IH), 11.63 (s, IH)

MS (ES+): m/z 524 (M+H)⁺ Example 137 Preparation of 4-(5-Acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)- N-[3-(4- methylpiperazin-l-yl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-2-amine

[0394] To a solution of 86 (60 mg, 0.135 mmol) in 2 rnL of anhydrous DMF was added one drop of Et₃N, followed by 0.5 rnL of a solution of acetyl chloride (11 mg, 0.135 mmol) in anhydrous dioxane (22 mg in 1 mL). The reaction mixture was stirred at ambient temperature for 30 min, then filtered through 0.2 u syringe filter and purified by reverse-phase preparative ΗPLC in CΗ₃CN/Η₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (30 mL). The solution was treated with saturated aqueous NaHCO₃ (2 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (30 mg, 45% yield).

[0395] ¹H NMR (500 MHz, DMSO-J₆, 80 ⁰C): δ 2.12 (s, 3H), 2.33 (s, 3H), 2.59 (br s, 4H), 2.94 (br s, 2H), 3.24 (t, J = 4.9 Hz, 4H), 3.80 (t, J = 5.2 Hz, 2H), 4.64 (s, 2H), 6.50 (dd, J = 8.0, 2.2 Hz, IH), 6.79 (dd, J = 3.4, 1.5 Hz, IH), 7.10 (t, J = 8.1 Hz, IH), 7.23 (dd, J = 3.5, 2.3 Hz, IH), 7.26 (dd, J = 9.0, 1.5 Hz, IH), 7.64 (t, J = 2.1 Hz, IH), 7.82 (s, IH), 8.58 (s, IH), 11.31 (s, IH)

MS (ES+): m/z 488 (M+H)⁺

Example 138 Preparation of 4-[5-(2,2-Dimethylpropanoyl)-4,5,6,7-tetrahydrothieno[3,2- c]pyridin-2-yl)- N-[3-(4-methylpiperazin-l-yl)phenyl]-7H-pyrrolo[2,3-<i]pyrimidin-2-amine

[0396] To a solution of 86 (60 mg, 0.135 mmol) in 2 niL of anhydrous DMF was added one drop of Et₃N, followed by 0.5 rnL of a solution of trimethylacetyl chloride (16 mg, 0.135 mmol) in anhydrous dioxane (32 mg in 1 mL). The reaction mixture was stirred at ambient temperature for 30 min, then filtered through 0.2 u syringe filter and purified by reverse-phase preparative HPLC in CH₃CN/H₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (30 mL). The solution was treated with saturated aqueous NaHCO₃ (2 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (34 mg, 47% yield).

[0397] ¹H NMR (500 MHz, DMSO-J₆): δ 1.25 (s, 9H), 2.28 (s, 3H), 2.54 (br s, 4H), 2.90 (br s, 2H), 318 (br s, 4H), 3.89 (t, J = 5.6 Hz, 2H), 4.70 (s, 2H), 6.48 (dd, J = 8.1, 2.1 Hz, IH), 6.86 (dd, J = 3.7, 1.8 Hz, IH), 7.09 (t, J= 8.1 Hz, IH), 7.26 (dd, J = 8.1, 1.2 Hz, IH), 7.30 (dd, J= 3.5, 2.4 Hz, IH), 7.70 (s, IH), 7.94 (s, IH), 9.00 (s, IH), 11.60 (s, IH)

MS (ES+): m/z 530 (M+H)⁺

Example 139 Preparation of N,N-Diethyl-2-(2-{ [3-(4-methylpiperazin-l-yl)phenyl]amino}- 7H-pyrrolo[2,3-(i]pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide

[0398] To a solution of 86 (60 mg, 0.135 mmol) in 2 niL of anhydrous DMF was added one drop of Et₃N, followed by 0.5 rnL of a solution of diethylcarbamyl chloride (18.3 mg, 0.135 mmol) in anhydrous dioxane (37 mg in 1 mL). The reaction mixture was stirred at ambient temperature for 30 min, then filtered through 0.2 u syringe filter and purified by reverse-phase preparative HPLC in CH₃CN/H₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (30 mL). The solution was treated with saturated aqueous NaHCO₃ (2 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (38 mg, 52% yield).

[0399] ¹H NMR (500 MHz, DMSO-J₆): δ 1.09 (t, J = 7.1 Hz, 6H), 2.28 (s, 3H), 2.54 (br s, 4H), 2.93 (t, J = 5.2 Hz, 2H), 3.15-3.20 (m, 8H), 3.47 (t, J = 5.5 Hz, 2H), 4.31 (s, 2H), 6.47 (dd, J = 8.1, 2.0 Hz, IH), 6.86 (dd, J= 3.7, 1.8 Hz, IH), 7.09 (t, J = 8.1 Hz, IH), 7.26 (dd, J = 8.1, 1.3 Hz, IH), 7.29 (dd, J= 3.5, 2.4 Hz, IH), 7.71 (t, J = 1.9 Hz, IH), 7.89 (s, IH), 9.00 (s, IH), 11.60 (s, IH)

MS (ES+): m/z 545 (M+H)⁺

Example 140 Preparation of N-[3-(4-Methylpiperazin-l-yl)phenyl]-4-[5-(pyridin-3- ylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl]-7H-pyrrolo[2,3-(i]pyrimidin-2-amine

[0400] To a solution of 86 (60 mg, 0.135 mmol) in 2 niL of anhydrous DMF was added one drop of Et₃N, followed by solid nicotinoyl chloride hydrochloride salt. The reaction mixture was stirred at ambient temperature for 30 min, then filtered through 0.2 u syringe filter and purified by reverse-phase preparative HPLC in CH₃CN/H₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (30 mL). The solution was treated with saturated aqueous NaHCO₃ (2 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (38 mg, 51% yield).

[0401] ¹H NMR (500 MHz, DMSO-J₆, 80 ⁰C): δ 2.29 (s, 3H), 2.55 (t, J = 4.7 Hz, 4H), 3.01 (t, J = 5.7 Hz, 2H), 3.22 (t, J = 4.9 Hz, 4H), 3.85 (br s, 2H), 4.73 (s, 2H), 6.49 (dd, J = 8.1, 2.0 Hz, IH), 6.79 (d, J = 2.0 Hz, IH), 7.10 (t, J = 8.1 Hz, IH), 7.22 (t, J = 2.8 Hz, IH), 7.26 (d, J = 8.2 Hz, IH), 7.50 (dd, J = 7.7, 4.9 Hz, IH), 7.61 (s, IH), 7.82 (s, IH), 7.89 (d, J= 7.8 Hz, IH), 8.54 (s, IH), 8.68 (d, J = 1.4 Hz, IH), 8.69 (s, IH), 11.28 (s, IH)

MS (ES+): m/z 551 (M+H)⁺

Example 141 Preparation of 4-[5-(Cyclopropylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2- c]pyridine-2-yl]-N-[3-(4-methylpiperazin-l-yl)phenyl]-7H-pyrrolo[2,3-(i]pyrimidin-2-amine

[0402] To a solution of 86 (60 mg, 0.135 mmol) in 2 niL of anhydrous DMF was added one drop of Et₃N, followed by 0.5 rnL of a solution of cyclopropylsulfonyl chloride (19.0 mg, 0.135 mmol) in anhydrous dioxane (38 mg in 1 mL). The reaction mixture was stirred at ambient temperature for 30 min, then filtered through 0.2 u syringe filter and purified by reverse-phase preparative HPLC in CH₃CN/H₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (30 mL). The solution was treated with saturated aqueous NaHCO₃ (2 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (37 mg, 50% yield).

[0403] ¹H NMR (500 MHz, DMSO-J₆): δ 0.96-0.99 (m, 4H), 2.29 (s, 3H), 2.56 (br s, 4H), 2.63-2.68 (m, IH), 3.02 (t, J = 5.5 Hz, 2H), 3.19 (br s, 4H), 3.62 (t, J = 5.8 Hz, 2H), 4.46 (s, 2H), 6.48 (dd, J = 8.2, 2.1 Hz, IH), 6.84 (dd, J= 3.6, 1.8 Hz, IH), 7.09 (t, J = 8.1 Hz, IH), 7.27 (dd, J = 8.1, 1.3 Hz, IH), 7.31 (dd, J = 3.5, 2.3 Hz, IH), 7.70 (t, J= 1.9 Hz, IH), 7.92 (s, IH), 9.02 (s, IH), 11.62 (s, IH)

MS (ES+): m/z 550 (M+H)⁺

Example 142 Preparation of N-[3-(4-Methylpiperazin-l-yl)phenyl]-4-[5-(morpholin-4- ylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl]-7H-pyrrolo[2,3-(i]pyrimidin-2-amine

[0404] To a solution of 86 (60 mg, 0.135 mmol) in 2 niL of anhydrous DMF was added one drop of Et₃N, followed by 0.5 rnL of a solution of morpholine-4-carbonyl chloride (20.0 mg, 0.135 mmol) in anhydrous dioxane (40 mg in 1 mL). The reaction mixture was stirred at ambient temperature for 30 min, then filtered through 0.2 u syringe filter and purified by reverse-phase preparative HPLC in CH₃CN/H₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (30 mL). The solution was treated with saturated aqueous NaHCO₃ (2 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (32 mg, 42% yield).

[0405] ¹H NMR (500 MHz, DMSO-J₆): δ 2.28 (s, 3H), 2.55 (br s, 4H), 2.93 (t, J = 5.2 Hz, 2H), 3.18-3.20 (m, 8H), 3.53 (t, J = 5.6 Hz, 2H), 3.62 (t, J = 4.5 Hz, 4H), 4.40 (s, 2H), 6.48 (dd, J = 8.2, 2.1 Hz, IH), 6.84 (dd, J= 3.7, 1.8 Hz, IH), 7.09 (t, J = 8.1 Hz, IH), 7.25 (dd, J = 8.1, 1.3 Hz, IH), 7.30 (dd, J= 3.6, 2.3 Hz, IH), 7.70 (t, J = 1.9 Hz, IH), 7.88 (s, IH), 9.00 (s, IH), 11.60 (s, IH)

MS (ES+): m/z 559 (M+H)⁺

Example 143 Preparation of N,N-Dimethyl-2-(2-{ [3-(4-methylpiperazin-l-yl)phenyl]amino}- 7H-pyrrolo[2,3-(i]pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-sulfonamide

[0406] To a solution of 86 (60 mg, 0.135 mmol) in 2 niL of anhydrous DMF was added one drop Of Et₃N, followed by neat dimethyl sulfamoyl chloride (23 mg, 0.161 mmol, 17.2 uL). The reaction mixture was stirred at ambient temperature for 30 min, then filtered through 0.2 u syringe filter and purified by reverse-phase preparative HPLC in CH₃CN/H₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (30 mL). The solution was treated with saturated aqueous NaHCO₃ (2 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (38 mg, 51% yield).

[0407] ¹H NMR (500 MHz, DMSO-J₆): δ 2.27 (s, 3H), 2.52 (br s, 4H), 2.79 (s, 6H), 2.97 (t, J = 5.5 Hz, 2H), 3.18 (br s, 4H), 3.60 (t, J = 5.7 Hz, 2H), 4.41 (s, 2H), 6.48 (dd, J = 8.2, 2.1 Hz, IH), 6.84 (dd, J = 3.6, 1.8 Hz, IH), 7.09 (t, J = 8.1 Hz, IH), 7.25 (dd, J = 8.1, 1.3 Hz, IH), 7.31 (dd, J = 3.4, 2.4 Hz, IH), 7.70 (t, J= 1.8 Hz, IH), 7.91 (s, IH), 9.01 (s, IH), 11.60 (s, IH)

MS (ES+): m/z 553 (M+H)⁺

Example 144 Preparation of 4-{5-[(Dimethylamino)acetyl]-4,5,6,7-tetrahydrothieno[3,2- c]pyridin-2-yl}-N-[3-(4-methylpiperazin-l-yl)phenyl]-7H-pyrrolo[2,3-(i]pyrimidin-2-amine

[0408] To a solution of 86 (60 mg, 0.135 mmol) in 2 niL of anhydrous DMF was added one drop of Et₃N, followed by solid dimethylaminoacetyl chloride hydrochloride salt (32 mg, 0.20 mmol). The reaction mixture was stirred at ambient temperature for 30 min, then filtered through 0.2 u syringe filter and purified by reverse-phase preparative HPLC in CH₃CN/H₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (30 mL). The solution was treated with saturated aqueous NaHCO₃ (2 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (26 mg, 36% yield).

[0409] ¹H NMR (500 MHz, DMSO-J₆, 80 ⁰C): δ 2.26 (s, 6H), 2.27 (s, 3H), 2.50-2.52 (m, 4H), 2.94 (br s, 2H), 2.99 (br s , 4H), 3.20 (s, 2H), 3.88 (t, J = 5.6 Hz, 2H), 4.68 (s, 2H), 6.49 (dd, J = 8.0, 2.1 Hz, IH), 6.79 (dd, J= 3.6, 1.6 Hz, IH), 7.10 (t, J = 8.1 Hz, IH), 7.22-7.25 (m, 2H), 7.63 (t, J= 2.0 Hz, IH), 7.81 (s, IH), 8.55 (s, IH), 11.30 (s, IH)

MS (ES+): m/z 531 (M+H)⁺

Example 145 Preparation of N-[3-(4-Methylpiperazin-l-yl)phenyl]-4-[5-(trifluoroacetyl)- 4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl]-7H-pyrrolo[2,3-(i]pyrimidin-2-amine

[0410] To a solution of 86 (60 mg, 0.135 mmol) in 2 niL of anhydrous DMF was added one drop of Et₃N, followed by neat trifluoroacetic anhydride (34 mg, 0.162 mmol, 22.5 uL). The reaction mixture was stirred at ambient temperature for 30 min, then filtered through 0.2 u syringe filter and purified by reverse-phase preparative HPLC in CH₃CN/H₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (30 mL). The solution was treated with saturated aqueous NaHCO₃ (2 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (39 mg, 53% yield).

[0411] ¹H NMR (500 MHz, DMSO-J₆, 80 ⁰C): δ 2.33 (s, 3H), 2.60 (br s, 4H), 3.03 (br s, 2H), 3.23-3.25 (m, 4H), 3.97 (br s, 2H), 4.80 (s, 2H), 3.55 (t, J = 5.7 Hz, 2H), 4.40 (s, 2H), 6.50 (dd, J = 8.0, 2.1 Hz, IH), 6.81 (dd, J = 3.5, 1.6 Hz, IH), 7.10 (t, J= 8.1 Hz, IH), 7.24- 7.27 (m, 2H), 7.62 (s, IH), 7.89 (s, IH), 8.61 (s, IH), 11.35 (s, IH)

MS (ES+): m/z 542 (M+H)⁺

Example 146 Preparation of Intermediates

87

^r/-Butyl 2-(2-{[4-(2-pyrrolidin-l-ylethoxy)phenyl]amino}-7H-pyrrolo[2,3- rf]pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (87)

[0412] To a 20 niL of microwave vial was charged with 7 (1.073 g, 3.0 mmol), Pd(PPh₃)₄ (347 mg, 0.3 mmol), 83 (0.85 g, 3.0 mmol), solid K₂CO₃ (0.83 g, 6.0 mmol) and with 20 mL of anhydrous DMF. The mixture was purged with argon gas for 10 min, then sealed and irradiated in a microwave (Initiator, Biotage) at 160 ⁰C for 50 min. The resulting reaction mixture was diluted with EtOAc (100 mL) and washed with H₂O (2 x 50 mL), brine (2 x 50 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo with ca. 15 g of silica gel. The loaded silica gel was taken to the ISCO system for purification using 80 g column and 0% to 20% MeOH gradient in DCM. Fractions, containing the product, were combined and concentrated in vacuo to give the title compound as a yellow solid (0.646 g, 38% yield).

88

N-[4-(2-Pyrrolidin-l-ylethoxy)phenyl]-4-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine- 2-yl)-7H-pyrrolo[2,3-rf]pyrimidin-2-amine (88)

[0413] Compound 87 (646 mg, 1.15 mmol) was treated with 40 mL of 50% TFA in CH₂Cl₂ for 10 min. The resulting solution was concentrated down in vacuo. The residue was re- dissolved in 10 mL of MeOH added to 100 mL of saturated aqueous NaHCO₃. The formed precipitate was collected, washed with water (2 x 40 niL) and dried in vacuo to give the title compound as a yellow solid (500 mg, 94% yield).

Example 147 Preparation of 4-(5-Acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-N-[4-(2- pyrrolidin-l-ylethoxy)phenyl]-7H-pyrrolo[2,3-(i]pyrimidin-2-amine

[0414] To a solution of 88 (46 mg, 0.1 mmol) in 2 mL of anhydrous DMF was added one drop of Et₃N, followed by 0.5 mL of solution of acetyl chloride (9.4 mg, 0.12 mmol) in anhydrous dioxane (20 mg in 1 mL). The reaction mixture was stirred at ambient temperature for 30 min, then filtered through 0.2 u syringe filter and purified by reverse-phase preparative ΗPLC in CΗ3CN/Η2O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (30 mL). The solution was treated with saturated aqueous NaHCO₃ (2 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a bright- yellow solid (40 mg, 79% yield).

[0415] ¹H NMR (500 MHz, DMSO-J₆, 80 ⁰C): δ 1.79 (br s, 4H), 2.12 (s, 3H), 2.72 (br s, 4H), 2.94 (br s, 4H), 3.80 (t, J = 5.3 Hz, 2H), 4.12 (t, J = 5.8 Hz, 2H), 4.64 (s, 2H), 6.76 (s, IH), 6.90 (d, J = 8.9 Hz, 2H), 7.19 (s, IH), 7.74 (d, J = 9.0 Hz, 2H), 7.79 (s, IH), 8.54 (s, IH), 11.26 (s, IH)

MS (ES+): m/z 503 (M+H)⁺

Example 148 Preparation of 4-[5-(Methylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2- yl]-N-[4-(2-pyrrolidin-l-ylethoxy)phenyl]-7H-pyrrolo[2,3-(i]pyrimidin-2-amine

[0416] To a solution of 88 (46 mg, 0.1 mmol) in 2 niL of anhydrous DMF was added one drop of Et₃N, followed by 0.5 rnL of solution of methanesulfonyl chloride (14 mg, 0.12 mmol) in anhydrous THF (28 mg in 1 mL). The reaction mixture was stirred at ambient temperature for 30 min, then filtered through 0.2 u syringe filter and purified by reverse-phase preparative HPLC in CH₃CN/H₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (50 mL). The solution was treated with saturated aqueous NaHCO₃ (2 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a bright- yellow solid (47 mg, 87% yield).

[0417] ¹H NMR (500 MHz, DMSO-J₆): δ 1.73 (br s, 4H), 2.66 (br s, 4H), 2.91 (br s, 2H), 2.98 (s, 3H), 3.02 (t, J = 5.5 Hz, 2H), 3.54 (t, J = 5.7 Hz, 2H), 4.08 (t, J = 5.7 Hz, 2H), 4.39 (s, 2H), 6.81 (dd, J = 3.7, 1.8 Hz, IH), 6.89 (d, J= 9.1 Hz, 2H), 7.26 (dd, J= 3.5, 2.4 Hz, IH), 7.76 (d, J = 9.1 Hz, 2H), 7.89 (s, IH), 9.00 (s, IH), 11.56 (s, IH)

MS (ES+): m/z 539 (M+H)⁺

Example 149 Preparation of N,N-Diethyl-2-(2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl] -amino }- 7H-pyrrolo[2,3-(i]pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide

[0418] To a solution of 88 (46 mg, 0.1 mmol) in 2 niL of anhydrous DMF was added one drop of Et₃N, followed by 0.5 rnL of solution of diethylcarbamyl chloride (16.8 mg, 0.12 mmol) in anhydrous THF (33 mg in 1 mL). The reaction mixture was stirred at ambient temperature for 30 min, then filtered through 0.2 u syringe filter and purified by reverse-phase preparative HPLC in CH₃CN/H₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (50 mL). The solution was treated with saturated aqueous NaHCO₃ (2 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a bright-yellow solid (42 mg, 75% yield).

[0419] ¹H NMR (500 MHz, DMSO-J₆): δ 1.09 (t, J = 7.1 Hz, 6H), 1.72 (br s, 4H), 2.63 (br s, 4H), 2.87 (br s, 2H), 2.93 (t, J = 5.1 Hz, 2H), 3.18 (q, J= 7.0 Hz, 4H), 3.46 (t, J= 5.5 Hz, 2H), 4.06 (t, J= 5.8 Hz, 2H), 4.31 (s, 2H), 6.83 (dd, J = 3.6, 1.7 Hz, IH), 6.88 (d, J= 9.1 Hz, 2H), 7.24 (dd, J = 3.4, 2.4 Hz, IH), 7.76 (d, J= 9.1 Hz, 2H), 7.87 (s, IH), 8.97 (s, IH), 11.54 (s, IH)

MS (ES+): m/z 560 (M+H)⁺

Example 150 Preparation of N,N-Bis-(l-methylethyl)-2-(2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl]-amino}-7H-pyrrolo[2,3-(i]pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridine-

5(4H)-carboxamide

[0420] To a solution of 88 (46 mg, 0.1 mmol) in 2 mL of anhydrous DMF was added one drop of Et₃N, followed by neat diisopropylcarbamyl chloride (20 mg, 0.12 mmol) in anhydrous TΗF (33 mg in 1 mL). The reaction mixture was stirred at ambient temperature for 30 min, then filtered through 0.2 u syringe filter and purified by reverse-phase preparative ΗPLC in CH₃CN/H₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (50 mL). The solution was treated with saturated aqueous NaHCO₃ (2 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a bright- yellow solid (57 mg, 97% yield).

[0421] ¹H NMR (500 MHz, DMSO-J₆): δ 1.24 (d, J = 6.6 Hz, 12H), 1.73 (br s, 4H), 2.66 (br s, 4H), 2.90 (br s, 2H), 2.93 (t, J = 5.2 Hz, 2H), 3.35 (t, J = 5.5 Hz, 2H), 3.67 (septet, J = 6.7 Hz, 2H), 4.07 (t, J = 5.8 Hz, 2H), 4.17 (s, 2H), 6.83 (dd, J = 3.6, 1.8 Hz, IH), 6.88 (d, J = 9.1 Hz, 2H), 7.24 (dd, J = 3.4, 2.4 Hz, IH), 7.76 (d, J = 9.1 Hz, 2H), 7.85 (s, IH), 8.98 (s, IH),

11.54 (s, IH)

MS (ES+): m/z 588 (M+H)⁺

Example 151 Preparation of 4-[5-(Pyridin-3-ylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2- c]pyridin-2-yl]-N-[4-(2-pyrrolidin-l-ylethoxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-2-amine

[0422] To a solution of 88 (46 mg, 0.1 mmol) in 2 mL of anhydrous DMF was added one drop of Et₃N, followed by solid nicotinoyl chloride hydrochloride salt (21.4 mg, 0.12 mmol). The reaction mixture was stirred at ambient temperature for 30 min, then filtered through 0.2 u syringe filter and purified by reverse-phase preparative ΗPLC in CΗ₃CN/Η₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (50 mL). The solution was treated with saturated aqueous NaHCO₃ (2 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a bright- yellow solid (42 mg, 74% yield). [0423] ¹H NMR (500 MHz, DMSO-J₆, 80 ⁰C): δ 1.71-1.75 (m, 4H), 2.62 (br s, 4H), 2.86 (t, J = 5.9 Hz, 2H), 3.01 (m, 2H), 3.84 (br s, 2H), 4.08 (t, J = 5.9 Hz, 2H), 4.73 (s, 2H), 6.76 (d, J = 2.1 Hz, IH), 6.89 (d, J = 9.1 Hz, 2H), 7.18 (dd, J= 3.5, 2.2 Hz, IH), 7.50 (dd, J = 8.0, 5.1 Hz, IH), 7.73 (d, J= 9.1 Hz, 2H), 7.81 (s, IH), 7.89 (dt, J = 5.8, 3.8 Hz, IH), 8.53 (s, IH), 8.67-8.69 (m, 2H), 11.24 (s, IH)

MS (ES+): m/z 566 (M+H)⁺

Example 152 Preparation of N-tert-Y$uty\-2-(2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl] amino }- 7H-pyrrolo[2,3-(i]pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide

[0424] To a solution of 88 (46 mg, 0.1 mmol) in 2 mL of anhydrous DMF was added neat tert-butyl isocyanate (12 mg, 0.12 mmol). The reaction mixture was stirred at ambient temperature for 30 min, then filtered through 0.2 u syringe filter and purified by reverse-phase preparative ΗPLC in CΗ₃CN/Η₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (50 mL). The solution was treated with saturated aqueous NaHCO₃ (2 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a bright-yellow solid (50 mg, 89% yield).

[0425] ¹H NMR (500 MHz, DMSO-J₆): δ 1.28 (s, 9H), 1.68-1.71 (m, 4H), 2.56 (br s, 4H), 2.81-2.85 (m, 4H), 3.64 (t, J= 5.5 Hz, 2H), 4.04 (t, J= 5.9 Hz, 2H), 4.46 (s, 2H), 5.92 (s, IH), 6.80 (dd, J = 3.6, 1.7 Hz, IH), 6.87 (d, J = 9.1 Hz, 2H), 7.24 (dd, J = 3.3, 2.5 Hz, IH), 7.75 (d, J= 9.1 Hz, 2H), 7.80 (s, IH), 8.97 (s, IH), 11.55 (s, IH)

MS (ES+): m/z 560 (M+H)⁺ Example 153 Preparation of 4-{5-[(5-Methylisoxazol-3-yl)carbonyl]-4,5,6,7- tetrahydrothieno[3,2-c]pyridin-2-yl}-N-[4-(2-pyrrolidin-l-ylethoxy)phenyl]-7H-pyrrolo[2,3- d]pyrimidin-2-amine

[0426] To a solution of 88 (46 mg, 0.1 mmol) in 2 rnL of anhydrous DMF was added 5- methyl-isoxazole-3-carbonyl chloride (12 mg, 0.12 mmol). The reaction mixture was stirred at ambient temperature for 30 min, then filtered through 0.2 u syringe filter and purified by reverse-phase preparative ΗPLC in CΗ₃CN/Η₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (50 mL). The solution was treated with saturated aqueous NaHCO₃ (2 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a bright- yellow solid (50 mg, 89% yield).

[0427] ¹H NMR (500 MHz, DMSO-J₆, 80 ⁰C): δ 1.72 (br s, 4H), 2.61 (br s, 4H), 2.84 (t, J = 5.9 Hz, 2H), 3.00 (br s, 2H), 3.97 (br s, 2H), 4.08 (t, J = 5.9 Hz, 2H), 4.82 (s, 2H), 6.45 (s, IH), 6.78 (s, IH), 6.89 (d, J = 8.9 Hz, 2H), 7.18 (s, IH), 7.73 (d, J = 8.8 Hz, 2H), 7.83 (br s, IH), 8.54 (s, IH), 11.25 (s, IH)

MS (ES+): m/z 570 (M+H)⁺

Example 154 Preparation of 4-[5-(4,6-Dimethoxy-l,3,5-triazin-2-yl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridin-2-yl]-N-[4-(2-pyrrolidin-l-ylethoxy)phenyl]-7H-pyrrolo[2,3- d]pyrimidin-2- amine

[0428] To a solution of 88 (46 mg, 0.1 mmol) in 2 niL of anhydrous DMF was added 1 drop of Et₃N, followed by solid 2-chloro-4,6-dimethoxytriazine (21 mg, 0.12 mmol). The reaction mixture was stirred at ambient temperature for 30 min, then filtered through 0.2 u syringe filter and purified by reverse-phase preparative HPLC in CH₃CN/H₂O system containing 0.1% of TFA. Fractions, containing the product, were combined and poured into EtOAc (50 mL). The solution was treated with saturated aqueous NaHCO₃ (2 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to give the title compound as a bright- yellow solid (45 mg, 75% yield).

[0429] ¹H NMR (500 MHz, DMSO-J₆, 80 ⁰C): δ 1.74-1.77 (m, 4H), 2.69 (br s, 4H), 2.92 (t, J = 5.8 Hz, 2H), 3.00 (t, J = 5.7 Hz, 2H), 3.92 (s, 6H), 4.12 (t, J = 5.9 Hz, 2H), 4.17 (t, J = 5.8 Hz, 2H), 4.92 (s, 2H), 6.79 (dd, J = 3.7, 1.4 Hz, IH), 6.89 (d, J = 9.1 Hz, 2H), 7.19 (dd, J = 3.5, 2.0 Hz, IH), 7.74 (d, J= 9.1 Hz, 2H), 7.85 (s, IH), 8.53 (s, IH), 11.28 (s, IH)

MS (ES+): m/z 600 (M+H)⁺

Example 155 Preparation of [3-(4-Methyl-piperazin- 1 -ylmethyl)-phenyl] - [4-(4-methyl- thiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-amine

[0430] A mixture of 1 (0.188 g, 0.755 mmol), 3-(4-methyl-piperazin-l-ylmethyl)- phenylamine dihydrochloride salt (0.294 g, 1.06 mmol), Pd₂(dba)₃ (0.069 g, 0.076 mmol), tri- tert-butyl-phosphine (IM in toluene, 0.151 mL, 0.15 mmol) and potassium te/t-butoxide (0.592 g, 5.29 mmol) were suspended in dioxane (2 mL) and DMF (2 mL) and microwaved at 160 ⁰C for 30 min. The reaction mixture was cooled to room temperature, diluted with DCM (30 mL), filtered and concentrated in vacuo. HPLC purification afforded the title compound (0.017 g, 6%).

[0431] ¹H NMR (500 MHz, DMSO-J₆): δ 2.14 (s, 3H), 2.32 (s, 3H), 3.43 (s, 2H), 6.82-6.86 (m, 2H), 7.20 (t, J = 7.8 Hz, IH), 7.28-7.31 (m, 2H), 7.39 (s, IH), 7.79 (d, J = 8.0 Hz, IH), 7.85 (s, IH), 7.91 (s, IH), 9.17 (s, IH), 11.6 (s, IH)

MS (ES+): m/z 419 (M+H)⁺

Example 156 Preparation of [4-(4-Methyl-thiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-(3- piperazin- 1 - yl -phenyl) - amine

[0432] A mixture of 1 (0.223 g, 0.896 mmol), 4-(3-amino-phenyl)-piperazine-l-carboxylic acid tert-butyX ester (0.322 g, 1.16 mmol), Pd₂(dba)₃ (0.082 g, 0.09 mmol), tri-tert-butyl- phosphine (IM in toluene, 0.18 mL, 0.18 mmol) and potassium tert-butoxide (0.502 g, 4.48 mmol) were suspended in dioxane (2 mL) and DMF (2 mL) and microwaved at 160 ⁰C for 30 min. The mixture was then cooled to room temperature and taken up in EtOAc, washed with water and brine. Organic phase was then dried, evaporated and purified on ΗPLC. Pure fractions were combined, diluted with EtOAc and neutralized with saturated sodium bicarbonate solution. Organic phase was evaporated and resulting residue treated with 20% TFA in DCM solution (ca. 15 mL). After 20 min, all solvents were removed. ΗPLC purification afforded the title compound (0.021 g, 6%). [0433] ¹H NMR (500 MHz, DMSO-J₆): δ 2.32 (s, 3H), 2.85-2.86 (m, 4H), 3.06-3.08 (m, 4H), 6.47 (d, J = 8.0 Hz, IH), 6.84-6.85 (m, IH), 7.07 (t, J = 7.8 Hz, IH), 7.29-7.31 (m, 2H), 7.39 (s, IH), 7.61 (s, IH), 7.91 (s, IH), 8.99 (s, IH), 11.6 (s, IH)

MS (ES+): m/z 391 (M+H)⁺

Example 157 Preparation of (4-Imidazol-l -ylmethyl -phenyl)- [4-(4-methyl-thiophen-2-yl)-7H- pyrrolo[2,3-J]pyrimidin-2-yl]-amine

[0434] A mixture of 1 (0.155 g, 0.622 mmol), 4-imidazol- 1-ylmethyl-phenylamine (0.14 g, 0.809 mmol), Pd₂(dba)₃ (0.057 g, 0.062 mmol), tri-te/t-butyl-phosphine (IM in toluene, 0.125 mL, 0.13 mmol) and potassium tert-butoxide (0.350 g, 3.11 mmol) were suspended in dioxane (2 mL) and DMF (2 mL) and microwaved at 160 ⁰C for 30 min. The reaction mixture was cooled to room temperature, diluted with DCM (30 mL), filtered and concentrated in vacuo. ΗPLC purification afforded the title compound (0.015 g, 6%).

[0435] ¹H NMR (500 MHz, DMSO-J₆): δ 2.32 (s, 3H), 5.01 (s, 2H), 6.85 (d, J = 2.6 Hz, IH), 6.89 (s, IH), 7.18-7.22 (m, 3H), 7.29-7.30 (m, IH), 7.39 (s, IH), 7.74 (s, IH), 7.87 (d, J = 8.6 Hz, 2H), 7.91 (s, IH), 9.26 (s, IH), 11.6 (s, IH)

MS (ES+): m/z 387 (M+H)⁺

Example 158 Preparation of Intermediates

89 3-Phenyl-thiophene (89) [0436] A mixture of 3-bromothiophene (5.89 g, 36.17 mmol), phenylboronic acid (3.53 g, 28.9 mmol), Pd(PPh₃ )₄ (3.34 g, 2.89 mmol) and solid sodium carbonate (3.83 g, 36.17 mmol) were suspended in DMF (100 mL) and heated to 130 ⁰C for 15 h. The reaction mixture was filtered while still hot, poured onto water and extracted with diethyl ether. Organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. This was then purified by silica gel flash chromatography affording the title compound (3.38 g, 58%).

90 4-Phenylthiophene-2-boronic acid (90)

[0437] A solution of 2,2,6,6-tetramethyl-piperidine (0.317 g, 2.25 mmol) in THF (10 mL) was chilled to -78 ⁰C and treated with tert-butyl lithium (1.7 molar solution in pentane, 1.38 mL, 2.34 mmol). 15 min after addition was complete, 89 (0.3 g, 1.88 mmol) was added as a solution in THF (3 mL). Neat triisopropyl borate (0.54 mL, 2.34 mmol) was then added via syringe. The reaction was then brought to room temperature and stirred for 30 min. This was then poured onto IN HCl and extracted with EtOAc. Organic phase was dried and evaporated to slightly sticky solids. Trituration with hexanes afforded title compound as a white solid (0.196 g, 51%).

Example 159 Preparation of [4-(4-Methyl-piperazin-l-yl)-phenyl]-[4-(4-phenyl-thiophen-2- yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-amine

[0438] A mixture of 90 (0.150 g, 0.735 mmol), 20 (0.193 g, 0.566 mmol), Pd(PPh₃)₄ (0.066 g, 0.06 mmol), 2M sodium carbonate (0.848 mL, 1.69 mmol) were suspended in DMF (4 mL) and microwaved at 170 ⁰C for 20 min. The reaction mixture was cooled to room temperature and syringe filtered. HPLC purification afforded the title compound (0.078 g, 30%).

[0439] ¹H NMR (500 MHz, DMSO-J₆): δ 2.22 (s, 3H), 2.46 (t, J = 4.8 Hz, 4H), 3.06 (t, J = 4.7 Hz, 4H), 6.89 (d, J = 9.0 Hz, 2H), 7.01 (d, J = 3.6 Hz, IH), 7.28 (d, J = 3.6 Hz, IH), 7.35 (t, J = 7.4 Hz, IH), 7.46 (t, J = 7.6 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 7.3 Hz, 2H), 8.11 (s, IH), 8.34 (s, IH), 8.97 (s, IH), 11.6 (br s, IH)

MS (ES+): m/z 467 (M+H)⁺

Example 160 Preparation of Interemediates

91

3-(3-Isopropyl-phenyl)-thiophene (91)

[0440] A mixture of 3-bromothiophene (3.07 g, 18.86 mmol), 3-isopropyl phenylboronic acid (4.02 g, 24.5 mmol), Pd(PPh₃)₄ (2.18 g, 1.9 mmol) and solid sodium carbonate (2 g, 18.9 mmol) were suspended in DMF (100 mL) and heated to 130 ⁰C for 3 h. The reaction mixture was cooled, poured onto water and extracted with EtOAc. Organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. This was then purified by silica gel flash chromatography affording the title compound (2.62 g, 69%).

92

3-(3-Isopropyl-phenyl)-thiophene-2-boronic acid (92)

[0441] A solution of 91 (0.900 g, 4.46 mmol) in THF (10 mL) was chilled to -78 ⁰C and treated with tert-buty\ lithium (1.7 molar solution in pentane, 3 mL, 5.12 mmol) and stirred for 30 min. Neat triisopropyl borate (1.23 mL, 5.34 mmol) was then added via syringe. The reaction was then brought to room temperature and stirred for 15 h. This was then poured onto IN HCl and extracted with EtOAc. Organic phase was dried and evaporated afford title compound as white solids (0.45 g, 41%).

Example 161 Preparation of {4-[4-(3-Isopropyl-phenyl)-thiophen-2-yl]-7H-pyrrolo[2,3- d]pyrimidin-2-yl } - [4-(4-methyl-piperazin- 1 -yl)-phenyl] -amine

[0442] A mixture of 92 (0.066 g, 0.268 mmol), 20 (0.076 g, 0.224 mmol), Pd(PPh₃)₄ (0.026 g, 0.022 mmol), 2M sodium carbonate (0.336 mL, 0.671 mmol) were suspended in DMF (4 mL) and microwaved at 170 ⁰C for 20 min. The reaction mixture was cooled to room temperature and syringe filtered. ΗPLC purification afforded the title compound (0.015 g,

13%).

[0443] ¹H NMR (500 MHz, DMSO-J₆): δ 1.28 (d, J = 6.9 Hz, 6H), 2.22 (s, 3h), 2.46 (t, J = 4.8 Hz, 4H), 2.97-3.00 (m, IH), 3.06 (t, J= 4.7 Hz, 4H), 6.90 (d, J= 9.1 Hz, 2H), 6.99-7.00 (m, IH), 7.23 (d, J = 3.9 Hz, IH), 7.27-7.28 (m, IH), 7.37 (t, J = 7.2 Hz, IH), 7.70-7.74 (m, 4H), 8.10 (s, IH), 8.32 (s, IH), 8.97 (s, IH), 11.58 (br s, IH)

MS (ES+): m/z 509 (M+H)⁺

Example 162 Preparation of Intermediates

93

4-(3-Thiophen-3-yl-benzenesulfonyl)-morpholine (93) [0444] A mixture of 3-bromothiophene (0.444 g, 2.72 mmol), 3-/V-morpholinylsulfonyl phenylboronic acid (0.960 g, 3.54 mmol), Pd(PPh₃)₄ (0.252 g, 0.218 mmol) and solid sodium carbonate (0.289 g, 2.72 mmol) were suspended in DMF (4 mL) and microwaved at 180 ⁰C for 20 min. The reaction mixture was then cooled, poured onto ice and resulting solids collected and dried (1 g, 99%).

94 4-(3-Thiophen-3-yl-benzenesulfonyl)-morpholine-2-boronic add (94)

[0445] A solution of 93 (1.05 g, 3.39 mmol) in THF (15 mL) was chilled to -78 ⁰C and treated with tert-butyl lithium (1.7 molar solution in pentane, 2.3 mL, 3.9 mmol) and stirred for 30 min. Neat triisopropyl borate (0.937 mL, 4.08 mmol) was then added via syringe. The reaction was then brought to room temperature and stirred for 15 h. This was then poured onto IN HCl and extracted with EtOAc. Organic phase was dried and evaporated afford title compound as a white solid (0.33 g, 28%).

Example 163 Preparation of {4-[4-(3-Isopropyl-phenyl)-thiophen-2-yl]-7H-pyrrolo[2,3- d]pyrimidin-2-yl } - [4-(4-methyl-piperazin- 1 -yl)-phenyl] -amine

[0446] A mixture of 94 (0.200 g, 0.568 mmol), 20 (0.130 g, 0.379 mmol), Pd(PPh₃)₄ (0.044 g, 0.038 mmol), 2M sodium carbonate (0.57 mL, 1.14 mmol) were suspended in DMF (4 mL) and microwaved at 170 ⁰C for 20 min. The reaction mixture was cooled to room temperature and syringe filtered. HPLC purification afforded the title compound (0.025 g, 11%).

[0447] ¹H NMR (500 MHz, DMSO-J₆): δ 2.23 (s, 3H), 2.95 (t, J = 4.8 Hz, 4H), 3.07 (t, J = 4.8 Hz, 4H), 3.65 (t, J = 4.7 Hz, 4H), 6.90 (d, J = 9 Hz, 2H), 7.01-7.02 (m, IH), 7.28-7.29 (m, IH), 7.70-7.78 (m, 4H), 8.08 (s, IH), 8.28 (d, J = 7.9 Hz, 2H), 8.33 (s, IH), 8.40 (s, IH), 8.99 (s, IH), 11.60 (br s, IH)

MS (ES+): m/z 616 (M+H)⁺

Example 164 Preparation of [3-(4-Methyl-piperazin-l-yl)-phenyl]-[4-(4-methyl-thiophen-2- yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-amine

[0448] A mixture of 47 (0.304 g, 0.889 mmol), 4-methylthiophene-2-boronic acid (0.158 g, 1.11 mmol), Pd(PPh₃ )₄ (0.082 g, 0.07 mmol) and solid sodium carbonate (0.188 g, 1.78 mmol) were suspended in DMF (5 mL) and microwaved at 170 ⁰C for 30 min. The reaction mixture was cooled to room temperature and syringe filtered. ΗPLC purification afforded the title compound (0.085 g, 24%).

[0449] ¹H NMR (500 MHz, DMSO-J₆): δ 2.23 (s, 3H), 2.32 (s, 3H), 2.46-2.48 (m, 4H), 3.15-3.16 (m, 4H), 6.48 (dd, J= 8.2, 2.2 Hz, IH), 6.84-6.85 (m, IH), 7.08 (t, J= 8.2 Hz, IH), 7.28-7.31 (m, 2H), 7.39 (s, IH), 7.64 (s, IH), 7.91 (s, IH), 9.00 (s, IH), 11.6 (s, IH)

MS (ES+): m/z 405 (M+H)⁺

Example 165 Preparation of {4-[5-(3,5-Dimethyl-isoxazol-4-yl)-thiophen-2-yl]-7H- pyrrolo[2,3-(i]pyrimidin-2-yl}-[3-(4-methyl-piperazin-l-yl)-phenyl]-amine

[0450] A mixture of 47 (0.170 g, 0.497 mmol), 35 (0.139 g, 0.621 mmol), Pd(PPh₃)₄ (0.046 g, 0.06 mmol) and solid sodium carbonate (0.106 g, 1 mmol) were suspended in DMF (5 mL) and microwaved at 170 ⁰C for 30 min. The reaction mixture was cooled to room temperature and syringe filtered. HPLC purification afforded the title compound (0.040 g, 17%).

[0451] ¹H NMR (500 MHz, DMSO-J₆): δ 2.19 (s, 3H), 2.39 (s, 3H), 2.42-2.43 (m, 4H), 2.59 (s, 3H), 3.13-3.15 (m, 4H), 6.48 (dd, J = 8.2, 2.2 Hz, IH), 6.87-6.89 (m, IH), 7.09 (t, J = 8.2 Hz, IH), 7.31-7.34 (m, 2H), 7.36 (d, J = 3.9 Hz, IH), 7.62 (t, J = 2.0 Hz, IH), 8.11 (d, J = 3.9 Hz, IH), 9.06 (s, IH), 11.7 (s, IH)

MS (ES+): m/z 486 (M+H)⁺

Example 166 Preparation of (4-Benzo[b]thiophen-2-yl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-[3- (4-methyl-piperazin- 1 -yl)-phenyl] -amine

[0452] A mixture of 47 (0.190 g, 0.560 mmol), benzo[£]thiophene-2-boronic acid (0.139 g, 0.621 mmol), Pd(PPh₃)₄ (0.051 g, 0.044 mmol) and solid sodium carbonate (0.118 g, 1.11 mmol) were suspended in DMF (5 mL) and microwaved at 170 ⁰C for 30 min. The reaction mixture was cooled to room temperature and syringe filtered. ΗPLC purification afforded the title compound (0.070 g, 27%). [0453] ¹H NMR (500 MHz, DMSO-J₆): δ 2.26 (s, 3H), 3.18-3.20 (m, 4H), 6.51 (dd, J = 8.3, 2.2 Hz, IH), 7.01-7.02 (m, IH), 7.12 (t, J = 8.2 Hz, IH), 7.33 (dd, J= 7.9, 2.0 Hz, IH), 7.39-7.40 (m, IH), 7.45-7.48 (m, IH), 7.69 (s, IH), 8.01-8.03 (m, 2H), 8.48 (s, IH), 9.12 (s, IH), 11.7 (s, IH)

MS (ES+): m/z 441 (M+H)⁺

Example 167 Preparation of [4-(5-Methyl-benzo[b]thiophen-2-yl)-7H-pyrrolo[2,3- J]pyrimidin-2-yl]-[3-(4-methyl-piperazin-l-yl)-phenyl]-amine

[0454] A mixture of 47 (0.190 g, 0.560 mmol), 5-methyl-benzo[b]thiophene-2-boronic acid (0.139 g, 0.621 mmol), Pd(PPh₃)₄ (0.051 g, 0.044 mmol) and solid sodium carbonate (0.118 g, 1.11 mmol) were suspended in DMF (5 mL) and microwaved at 170 ⁰C for 30 min. The reaction mixture was cooled to room temperature and syringe filtered. ΗPLC purification afforded the title compound (0.050 g, 19%).

[0455] ¹H NMR (500 MHz, DMSO-J₆): δ 2.24 (s, 3H), 2.46 (s, 3H), 3.18-3.19 (m, 4H), 6.50 (dd, J = 8.3, 2.2 Hz, IH), 6.98-6.99 (m, IH), 7.11 (t, J = 8.4 Hz, IH), 7.29-7.34 (m, 2H), 7.38-7.39 (m, IH), 7.69 (s, IH), 7.80 (s, IH), 7.90 (d, J = 8.2 Hz, IH), 8.39 (s, IH), 9.11 (s, IH), 11.7 (s, IH)

MS (ES+): m/z 455 (M+H)⁺

Example 168 Preparation of Intermediates

95

2-{2-[4-(2-Methyl-imidazol-l-ylmethyl)-phenylamino]-7H-pyrrolo[2,3- rf]pyrimidin-4-yl}-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid /er/- butyl ester (95)

[0456] A mixture of 39 (0.670 g, 1.98 mmol), 83 (0.671 g, 2.37 mmol), Pd(PPh₃)₄ (0.228 g, 0.198 mmol) and solid sodium carbonate (0.418 g, 3.95 mmol) were suspended in DMF (12 mL) and microwaved at 170 ⁰C for 30 min. The reaction mixture was cooled to room temperature, poured onto water and extracted with ethyl acetate. Organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. This was then purified by silica gel flash chromatography affording the title compound (0.85 g, 79%).

96

[4-(2-Methyl-imidazol-l-ylmethyl)-phenyl]-[4-(4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-2-yl)-7H-pyrrolo[2,3-rf]pyrimidin-2-yl]-amine (96)

[0457] A solution of 95 (0.850 g, 1.57 mmol) in DCM (1OmL) was treated with a 20% solution of TFA in DCM (15mL). After stirring at room temperature for 3 h, solvents were removed. Resulting red syrup was diluted with water and pH was adjusted to -10. Resulting yellow precipitate was collected and dried (0.55 g, 79%). Example 169 Preparation of 2-{2-[4-(2-Methyl-imidazol-l-ylmethyl)-phenylamino]-7H- pyrrolo[2,3-(i]pyrimidin-4-yl}-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid diethylamide

[0458] A mixture of 96 (0.052 g, 0.118 mmol), diethycarbamoyl chloride (0.017 g, 0.124 mmol), and TEA (0.035 mL, 0.248 mmol) were suspended in DMF (2 mL) and stirred for 1 h. The reaction mixture then syringe filtered and ΗPLC purification afforded the title compound (0.039 g, 61%).

[0459] ¹H NMR (500 MHz, DMSO-J₆): δ 1.09 (t, J= 7.0 Hz, 6H), 2.27 (s, 3H), 2.93-2.95 (m, 2H), 3.16-3.20 (m, 4H), 3.45-3.47 (m, 2H), 4.30 (s, 2H), 5.05 (s, 2H), 6.77 (br s, IH), 6.86-6.87 (m, IH), 7.10-7.13 (m, 3H), 7.29-7.30 (m, IH), 7.86-7.89 (m, 3H), 9.24 (s, IH), 11.6 (s, IH)

MS (ES+): m/z 541 (M+H)⁺

Example 170 Preparation of Intermediates

97

Trimethyl-thiophen-3-ylethynyl-silane (97)

[0460] A solution of 3-bromothiophene (2.56 g, 36.17 mmol) in TEA (10 mL) and DMF (2 mL) was treated with copper iodide (0.300 g, 1.57 mmol) and purged with argon for 3 min. Ethynyl-trimethylsilane (2.31 g, 23.6 mmol) and PdCl₂(PPh₃)₂ (1.10 g, 1.57 mmol) were then added and microwaved at 140 ⁰C for 15 min. The reaction mixture was diluted with DCM (20 rnL), filtered and evaporated. This was then purified by silica gel flash chromatography to afford the title compound as an amber oil (1.86 g, 66%).

98

4-((Trimethylsilyl)ethynyl)thiophen-2-ylboronic acid (98)

[0461] A solution of 97 (0.206 g, 1.14 mmol) and triisopropyl borate (0.395 mL, 1.72 mmol) in THF (6mL) was chilled to -10 ⁰C and treated with LDA (1.5 M solution in cyclohexane, 1.53 mL, 2.29 mmol). The reaction was removed from cooling bath and allowed to come to room temperature and stir for 16 h. This was then poured onto IN HCl, stirred vigorously for 15 min and then extracted with EtOAc. Organic phase was dried and evaporated to afford title compound as brown oil (0.176 g, 68%).

99

[4-(2-Methyl-imidazol-l-ylmethyl)-phenyl]-[4-(4-trimethylsilanylethynyl- thiophen-2-yl)-7H-pyrrolo[2,3-rf]pyrimidin-2-yl]-amine (99)

[0462] A mixture of 39 (0.266 g, 0.786 mmol), 98 (0.176 g, 0.786 mmol), Pd(PPh₃)₄ (0.091 g, 0.079 mmol) and solid sodium carbonate (0.167 g, 1.57 mmol) were suspended in DMF (5 mL) and microwaved at 170 ⁰C for 30 min. The reaction mixture was cooled to room temperature and poured onto ice water. Resulting grey precipitate collected and dried (0.25 g, 66%). Example 171 Preparation of [4-(4-Ethynyl-thiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]- [4-(2-methyl-imidazol- 1 -ylmethyl)-phenyl] -amine

[0463] Compound 99 (0.147 g, 0.305 mmol) was suspended in MeOH (3 mL) and treated with solid K₂CO₃ (0.084 g, 0.609 mmol) and stirred for 3 h. Reaction was diluted with DCM (10 mL), filtered and evaporated. ΗPLC purification afforded the title compound (0.009 g,

7%).

[0464] ¹H NMR (500 MHz, DMSO-J₆): δ 2.26 (s, 3H), 4.24 (s, IH), 5.05 (s, 2H), 6.74 (s, IH), 6.91-6.92 (m, IH), 7.09-7.12 (m, 3H), 7.32-7.33 (m, IH), 7.84-7.86 (m, 2H), 8.06-8.07 (m, 2H), 9.32 (s, IH), 11.7 (s, IH)

MS (ES+): m/z 411 (M+H)⁺

Example 172 Preparation of (2-{2-[4-(2-Methyl-imidazol-l-ylmethyl)-phenylamino]-7H- pyrrolo[2,3-<i]pyrimidin-4-yl}-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-pyridin-3-yl- methanone

[0465] A mixture of 96 (0.063 g, 0.143 mmol), nicotinoyl chloride dihydrochloride (0.029 g, 0.164 mmol), and TEA (0.068 mL, 0.499 mmol) were suspended in DMF (2 mL) and stirred for 1 h. The reaction mixture was then syringe filtered. HPLC purification afforded the title compound (0.035 g, 45%).

[0466] ¹H NMR (500 MHz, DMSO-J₆): δ 2.27 (s, 3H), 2.99 (br s, 2H), 3.66 (br s, 2H), 4.01 (br s, IH), 4.61 (br s, IH), 4.81 (br s, IH), 5.05 (s, 2H), 6.77 (br s, IH), 7.10-7.12 (m, 3H), 7.25-7.32 (m, IH), 7.51-7.54 (m, IH), 7.82-7.87 (m, 2H), 7.93-7.99 (m, 2H), 8.68-8.71 (m, 2H), 9.26 (br s, IH), 11.58-11.62 (m, IH)

MS (ES+): m/z 547 (M+H)⁺

Example 173 Preparation of N-(4-((2-methyl-lH-imidazol-l-yl)methyl)phenyl)-4-(5-

(methylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2- amine

[0467] A mixture of 96 (0.068 g, 0.154 mmol), methane sulfonyl chloride (0.019 g, 0.162 mmol), and TEA (0.053 mL, 0.385 mmol) were suspended in DMF (2 mL) and stirred for 1 h. The reaction mixture was then syringe filtered. HPLC purification afforded the title compound (0.040 g, 50%).

[0468] ¹H NMR (500 MHz, DMSO-J₆): δ 2.27 (s, 3H), 2.98 (s, 3H), 3.01-3.03 (m, 2H), 3.53-3.55 (m, 2H), 4.40 (br s, 2H), 5.05 (s, 2H), 6.75 (s, IH), 6.84-6.85 (m, IH), 7.10-7.12 (m, 3H), 7.30-7.3 l (m, IH), 7.86 (d, J = 8.4 Hz, 2H), 7.92 (s, IH), 9.26 (s, IH), 11.6 (s, IH)

MS (ES+): m/z 520 (M+H)⁺

Example 174 Preparation of 2-{2-[4-(2-Methyl-imidazol-l-ylmethyl)-phenylamino]-7H- pyrrolo[2,3-<i]pyrimidin-4-yl}-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid ethylamide

[0469] A mixture of 96 (0.061 g, 0.138 mmol) and ethyl isocyanate (0.011 g, 0.152 mmol) were suspended in DMF (2 rnL) and stirred for 1 h. The reaction mixture was then syringe filtered. HPLC purification afforded the title compound (0.048 g, 68%).

[0470] ¹H NMR (500 MHz, DMSO-J₆): δ 1.04 (t, J= 7.2 Hz, 3H), 2.26 (s, 3H), 2.84-2.86 (m, 2H), 3.06-3.11 (m, 2H), 3.65-3.67 (m, 2H), 4.49 (br s, 2H), 5.05 (s, 2H), 6.63-6.65 (m, IH), 6.74 (s, IH), 6.82-6.84 (m, IH), 7.29-7.30 (m, IH), 7.83-7.87 (m, 3H), 9.24 (s, IH), 11.6 (s, IH)

MS (ES+): m/z 513 (M+H)⁺

Example 175 Preparation of 2-{2-[4-(2-Methyl-imidazol-l-ylmethyl)-phenylamino]-7H- pyrrolo[2,3-<i]pyrimidin-4-yl}-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid tert- butylamide

[0471] A mixture of 96 (0.054 g, 0.122 mmol) and tert-butyl isocyanate (0.013 g, 0.135 mmol) were suspended in DMF (2 mL) and stirred for 1 h. The reaction mixture was then syringe filtered. ΗPLC purification afforded the title compound (0.043 g, 65%). [0472] ¹H NMR (500 MHz, DMSO-J₆): δ 1.28 (s, 9H), 2.27 (s, 3H), 2.84-2.86 (m, 2H), 3.63-3.65 (m, 2H), 4.46 (br s, 2H), 5.05 (s, 2H), 5.93 (s, IH), 6.75 (s, IH), 6.83-6.84 (m, IH), 7.09-7.12 (m, 3H), 7.29-7.30 (m, IH), 7.83-7.87 (m, 3H), 9.24 (s, IH), 11.6 (s, IH)

MS (ES+): m/z 541 (M+H)⁺

Example 176 Preparation of Intermediate

100

[3-(4-Methyl-piperazine-l-sulfonyl)-phenyl]-[4-(4-methyl-thiophen-2-yl)-7- (toluene-4-sulfonyl)-7H-pyrrolo[2,3-rf]pyrimidin-2-yl]-amine (100)

[0473] A mixture of 9 (0.292 g, 0.724 mmol), 3-(4-methyl-piperazine-l-sulfonyl)- phenylamine (0.240 g, 0.941 mmol), Pd₂(dba)₃ (0.066 g, 0.072 mmol), Xantphos (0.084 g, 0.145 mmol) and cesium carbonate (0.708 g, 2.17 mmol) were suspended in DMF (5 mL) and microwaved at 160 ⁰C for 15 min. The reaction mixture was cooled to room temperature and poured onto ice water. Resulting beige precipitate collected and dried (0.45 g, 55%).

Example 177 Preparation of [3-(4-Methyl-piperazine-l-sulfonyl)-phenyl]-[4-(4-methyl- tmophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-amine

[0474] A stirring solution of 100 (0.260 g, 0.418 mmol) in MeOH (5 niL) was treated with cesium carbonate (0.400 g, 1.22 mmol). After 7 h, reaction was poured onto ethyl acetate (25 mL) and washed with water and brine. Orgainc phase was dried over sodium sulfate, filtered and evaporated. HPLC purification afforded the title compound (0.038 g, 19%).

[0475] ¹H NMR (500 MHz, DMSO-J₆): δ 2.12 (s, 3H), 2.33 (s, 3H), 3.36 (br s, 4H), 2.95 (br s, 4H), 6.88-6.89 (m, IH), 7.20 (dd, J = 6.4, 1.0 Hz, IH), 7.35-7.36 (m, IH), 7.42 (s, IH), 7.53 (t, J = 7.9 Hz, IH), 7.97 (s, IH), 8.14 (dd, J = 8.3, 1.8 Hz, IH), 8.48 (t, J= 1.9 Hz, IH), 9.67 (s, IH)

MS (ES+): m/z 469 (M+H)⁺

Example 178 Preparation of (5-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylthiophen-2-yl)methanol

[0476] A mixture of 4-(4-methylpiperazin-l-yl)benzenamine (46 mg, 0.24 mmol), 78 (90 mg, 0.2 mmol), Pd(OAc)₂ (5.0 mg, 0.02 mmol), P(J-Bu)₃ (400 μL of 1 M in toluene, 0.04 mmol) in triethylamine (28 μL, 5 mmol) and DMF (3 ml) was irradiated with microwave at 160 ⁰C for 45 min. The crude reaction mixture was purified using preparative ΗPLC to give Buchwald coupling product (75 mg, 64 %). The crude product (69 mg, 0.11 mmol) was treated with sodium borohydride (41 mg, 1.1 mmol) in methanol for 10 min. The reaction mixture was quenched with IN hydrochloric acid (1.0 mL) and evaporated. The crude residue was heated under reflux with Na₂CO₃ (530 mg, 5.0 mmol) for 16 h. The reaction mixture was cooled to room temperature and purified using preparative ΗPLC. The desired fractions were combined, triturated with dichloromethane and aqueous saturated NaHCO₃. The organic layer was separated, dried (Na₂SO₄) and concentrated to give the title compound as a yellow solid (8 mg, 17%). [0477] ¹H NMR (500 MHz, DMSO-J₆): δ 1.80-1.90 (m, 2H), 2.23 (s, 3H), 2.80-2.91 (m, 2H), 3.40-3.48 (m, 2H), 4.15-4.25 (m, 2H), 4.65 (s, 2H), 6.85-6.90 (m, IH), 7.30-7.36 (m, IH), 7.39 (d, J = 8.5 Hz, 2H), 7.84 (s, IH), 8.01 (d, J = 8.6 Hz, 2H), 9.14 (br s, IH), 9.41 (s, IH), 11.56 (s, IH)

MS (ES+): m/z 434 (M+H)⁺

Example 179 Preparation of 3-Methyl-5-{2-[4-(methyl-piperazin-l-yl)phenylamino]-7H- pyrrolo[2,3-J]pyrimidin-4-yl}-thiophene-2-carbaldehyde oxime

[0478] Compound 78 (618 mg, 1.5 mmol), 4-(4-methylpiperazin-l-yl)benzenamine (285 mg, 1.5 mmol), Pd(OAc)₂ (33 mg, 0.15 mmol), and P(J-Bu)₃ (300 μL of 1 M in toluene, 0.3 mmol) in triethylamine (2.0 mL, 15 mmol) and DMF (3 ml) was irradiated with microwave at 160 ⁰C for 25 min. The crude reaction mixture was purified using small column. The crude resulting solid was taken in 20 mL of ethanol and treated with hydroxylamine hydrochloride (90 mg, 1.3 mmol) and Na₂CO₃ (275 mg, 2.6 mmol) under reflux for 16 h. The reaction mixture was cooled to room temperature and purified using preparative ΗPLC. The desired fractions combined, triturated with dichloromethane and aqueous saturated NaHCO₃. The organic layer was separated, dried (Na₂SO₄) and concentrated to give the title compound as a dark brown solid (21 mg, 17%).

[0479] ¹H NMR (500 MHz, DMSO-J₆): δ 1.55-1.73 (m, 4H), 1.77-1.90 (m, 2H), 2.46 (s, 3H), 2.80-2.94 (m, 2H), 6.88-6.92 (m, IH), 7.33-7.42 (m, 3H), 7.40 (d, J = 8.5 Hz, 2H), 7.93 (d, J = 10.0 Hz, 2H), 8.00 (d, J = 3.9 Hz, 2H), 9.25-9.35 (br s, IH), 9.51 (s, IH)

MS (ES+): m/z 447 (M+H)⁺ Example 180 Preparation of (5-(2-(4-(Moφholinomethyl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3 methyl thiophen-2-yl)methanol

[0480] A mixture of 4-(morpholinomethyl)benzenamine (115 mg, 0.6 mmol), 78 (223 mg, 0.5 mmol), Pd(OAc)₂ (11 mg, 0.05 mmol), P(^-Bu)₃ (100 μL of 1 M in toluene, 0.1 mmol) in triethylamine (700 μL, 5 mmol) and DMF (3 ml) was irradiated with microwave at 180 ⁰C for 45 min. The crude reaction mixture was purified using ISCO to give Buchwald coupling product (72 mg, 12%). The crude product (55 mg, 0.9 mmol) was treated with sodium borohydride (38 mg, 1.0 mmol) in methanol (20 mL) for 10 min. The reaction mixture was quenched with IN hydrochloric acid (1.0 mL) and evaporated. The crude solid was heated under reflux with Na₂CO₃ (530 mg, 5.0 mmol) for 16 h. The reaction mixture was cooled to room temperature and purified using preparative ΗPLC. The desired fractions were combined, triturated with dichloromethane and aqueous saturated NaHCO₃. The organic layer was separated, dried (Na₂SO₄) and concentrated to give the title compound as a yellow solid (6 mg, 14%).

[0481] ¹H NMR (500 MHz, DMSO-J₆): δ 2.22 (s, 3H), 2.34 (br s, 4H), 3.39 (s, 2H), 3.56 (t, J = 7.0 Hz, 4H), 4.65 (d, J = 5.0 Hz, 2H), 5.50 (t, J= 2.8 Hz, IH), 6.81-6.83 (m, IH), 7.18 (d, J= 8.5 Hz, 2H), 7.25-7.29 (m, IH), 7.81 (s, IH), 7.83 (d, J= 8.5 Hz, 2H), 9.15 (s, IH), 11.57 (s, IH)

MS (ES+): m/z 436 (M+H)⁺

Example 181 Preparation of (5-(2-(3-(Morpholinomethyl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl) 3-methylthiophen-2-yl)methanol

[0482] A mixture of 3-(morpholinomethyl)benzenamine (46 mg, 0.24 mmol), 78 (90 mg, 0.2 mmol), Pd(OAc)₂ (5.0 mg, 0.02 mmol), P(J-Bu)₃ (400 μL of 1 M in toluene, 0.04 mmol) in triethylamine (28 μL, 5 mmol) and DMF (3 ml) was irradiated with microwave at 160 oC for 45 min. The crude reaction mixture was purified using preparative HPLC to give Buchwald coupling product (75 mg, 64 %). The crude product (69 mg, 0.11 mmol) was treated with sodium borohydride (41 mg, 1.1 mmol) in methanol for 10 min. The reaction mixture was quenched with IN hydrochloric acid (1.0 mL) and evaporated. The crude residue was heated under reflux with Na₂CO₃ (530 mg, 5.0 mmol) for 16 h. The reaction mixture was cooled to room temperature and purified using preparative HPLC. The desired fractions were combined, triturated with dichloromethane and aqueous saturated NaHCO₃. The organic layer was separated, dried (Na₂SO₄) and concentrated to give the title compound as a yellow solid (8 mg, 17%).

[0483] ¹H NMR (500 MHz, DMSO-J₆): δ 2.23 (s, 3H), 2.39 (br s, 4H), 3.46 (s, 2H), 3.56 (t, J = 7.0 Hz, 4H), 4.65 (d, J = 5.0 Hz, 2H), 5.49 (t, J= 5.5 Hz, IH), 5.75 (s, IH), 6.80-6.87 (m, 2H), 7.21 (t, J= 7.5 Hz, IH), 7.26-7.36 (m, IH), 7.77 (d, J = 15.0 Hz, IH), 7.82 (s, IH), 7.89 (br s, IH), 9.15 (s, IH), 11.56 (s, IH)

MS (ES+): m/z 436 (M+H)⁺

Example 182 Preparation of l-(5-(2-(3-(Moφholinomethyl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylthiophen-2-yl)propan- 1 -ol

[0484] Compound 78 (600 mg, 1.5 mmol) was treated with ethyl magnesium bromide (ImL of 1.3 M THF solution) at room temperature for 30 min. The reaction mixture quenched with IN hydrochloric acid (500 μL), evaporated and purified using ISCO to give l-(5-(2-chloro-7- tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylthiophen-2-yl)propan-l-ol (540 mg, 78%) as a brown solid. A mixture of the above solid (135 mg, 0.3 mmol), 3-

(morpholinomethyl)benzenamine (67 mg, 0.35 mmol), Pd(OAc)₂ (6.5 mg, 0.03 mmol), P(t- Bu)₃ (60 μL of 1 M in toluene, 0.06 mmol) in triethylamine (400 μL, 5 mmol) and DMF (3 ml) was irradiated with microwave at 160 ⁰C for 45 min. The crude reaction mixture was purified using preparative ΗPLC to give a desired coupling product (59 mg, 33 %). The solid was taken in methanol (30 mL) and heated under reflux with Na₂CO₃ (530 mg, 5.0 mmol) for 16 h. The reaction mixture was cooled to room temperature, evaporated and purified using preparative ΗPLC. The desired fractions combined, triturated with dichloromethane and aqueous saturated NaHCO₃. The organic layer was separated, dried (Na₂SO₄) and concentrated to give the title compound as a yellow solid (22 mg, 50%).

[0485] ¹H NMR (500 MHz, DMSO-J₆): δ 0.91 (t, J = 7.6 Hz, 3H), 1.66-1.82 (m, 2H), 2.24 (s, 3H), 2.39 (br s, 4H), 3.47 (s, 2H), 3.56 (t, J = 4.5 Hz, 4H), 4.80 (t, J = 6.5 Hz, IH), 6.83 (d, J= 3.7 Hz, IH), 6.84 (d, J= 8.5 Hz, 2H), 7.20 (t, J= 9.5 Hz, IH), 7.26 (d, J= 3.5 Hz, IH), 7.70 (br d, J = 8.0 Hz, IH), 7.78 (s, IH), 7.98 (br s, IH), 9.10 (s, IH), 11.56 (s, IH)

MS (ES+): m/z 464 (M+H)⁺

Example 183 Preparation of 2-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)benzo[b]thiophene-6-carbonitrile

[0486] A mixture of 20 (166 mg, 0.5 mmol), 30 (121 mg, 0.6 mmol), Pd₂(dba)₃ (45 mg, 0.05 mmol), (2-biphenyl)dicyclohexyl phosphine (35 mg, 0.1 mmol) and Na₂CO₃ (159 mg, 1.5 mmol) in Dioxane-DMF (3 ml; 8:2 v/v) was irradiated with microwave at 160 °C for 45 min. The crude reaction mixture was purified using preparative HPLC. The desired fractions were combined, triturated with DCM and aqueous saturated NaHCO₃. The organic layer was separated, dried (Na₂SO₄) and concentrated to give the title compound as a brick red solid (18 mg, 8%).

[0487] ¹H NMR (500 MHz, DMSO-J₆): δ 2.22 (s, 3H), 2.47 (t, J = 5.0 Hz, 4H), 3.07 (t, J = 5.0 Hz, 4H), 6.91 (d, J = 9.0 Hz, 2H), 7.00 (d, J = 3.5 Hz, IH), 7.39 (d, J = 3.6 Hz, IH), 7.72 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 9.5 Hz, IH), 8.15 (d, J = 10.0 Hz, IH), 8.58 (s, IH), 8.69 (d, J = 1.0 Hz, IH), 9.10 (s, IH), 11.72 (s, IH)

MS (ES+): m/z 466 (M+H)⁺

Example 184 Preparation of 2-(2-(3-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)benzo[b]thiophene-6-carbonitrile

[0488] A mixture of 47 (83 mg, 0.25 mmol), 30 (61 mg, 0.3 mmol), Pd₂(dba)₃ (27 mg, 0.03 mmol), (2-biphenyl)dicyclohexyl phosphine (21 mg, 0.06 mmol) and Na₂CO₃ (79 mg, 0.75 mmol) in Dioxane-DMF (3 ml; 8:2 v/v) was irradiated with microwave at 160 ⁰C for 45 min. The crude reaction mixture was purified using preparative HPLC. The desired fractions were combined, triturated with DCM and aqueous saturated NaHCO₃. The organic layer was separated, dried (Na₂SO₄) and concentrated to give the title compound as a bright yellow solid (54 mg, 47%).

[0489] ¹H NMR (500 MHz, DMSO-J₆): δ 2.24 (s, 3H), 2.43-2.50 (m, 4H superimposed with DMSO), 3.17 (t, J = 5.0 Hz, 4H), 6.45-6.57 (m, IH), 7.03 (dd, J = 3.3, 1.5 Hz, IH), 7.12 (d, J = 8.1 Hz, IH), 7.37 (dd, J = 8.5, 1.5 Hz, IH), 7.42-7.47 (m, IH), 7.54-7.60 (m, IH), 7.82 (d, J = 8.5 Hz, IH), 8.16 (d, J = 6.5 Hz, IH), 8.60 (s, IH), 8.68 (s, IH), 9.18 (s, IH), 11.80 (s, IH)

MS (ES+): m/z 466 (M+H)⁺

Example 185 Preparation of 2-(2-(3-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)benzo[b]thiophene-5-carbonitrile

[0490] A mixture of 47 (83 mg, 0.25 mmol), 75 (61 mg, 0.3 mmol), Pd₂(dba)₃ (27 mg, 0.03 mmol), (2-biphenyl)dicyclohexyl phosphine (21 mg, 0.06 mmol) and Na₂CO₃ (79 mg, 0.75 mmol) in Dioxane-DMF (3 ml; 8:2 v/v) was irradiated with microwave at 160 ⁰C for 45 min. The crude reaction mixture was purified using preparative ΗPLC. The desired fractions were combined, triturated with DCM and aqueous saturated NaHCO₃. The organic layer was separated, dried (Na₂SO₄) and concentrated to give the title compound as a yellow solid (12 mg, 10%). [0491] ¹H NMR (500 MHz, DMSO-J₆): δ 2.24 (s, 3H), 2.43-2.50 (m, 4H superimposed with DMSO), 3.15-3.24 (m, 4H), 6.52 (dd, J = 8.5, 1.9 Hz, IH), 6.98 (d, J = 3.3 Hz, IH), 7.12 (t, J= 8.5 Hz, IH), 7.34 (dd, J= 8.5, 1.5 Hz, IH), 7.45 (d, J = 3.8 Hz, IH), 7.60 (br s, IH), 7.82 (dd, J= 8.0, 1.5 Hz, IH), 8.28 (d, J = 8.5 Hz, IH), 8.48 (s, IH), 8.57 (s, IH), 9.18 (s, IH), 11.79 (s, IH)

MS (ES+): m/z 466 (M+H)⁺

Example 186 Preparation of Intermediate

101 5-Pentanoylbenzo[Z>]thiophen-2-yl-2-boronic acid (101)

[0492] The title product was isolated as a by-product of the following reaction. To a solution of benzo[b]thiophene-5-carbonitrile (0.5 g, 3.1 mmol) in THF (10 mL) cooled at -78 ⁰C under argon atmosphere was added ra-BuLi (2.5 M in hexanes; 2.0 mL, 5.0 mmol). The mixture was stirred at the same temperature for 15 min and tri-isopropylborate added (1.2 mL, 5.2 mmol). The resulting mixture was stirred at at -78 ⁰C for 5 min and then stirred at RT for 1 h. The reaction was quenched with IM HCl until pH~l and the mixture stirred for 15 min. The mixture was extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated, the residue re-dissolved in EtOAc and precipitated with hexanes. After filtration, the title compound and 5-cyanobenzo[b]thiophen-2-yl-2-boronic acid were obtained as a mixture (off- white solid, 0.61 g), which was used in the next step without purification.

Example 187 Preparation of l-(2-(2-(3-(4-Methylpiperazin-l-yl)phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)benzo[b]thiophen-5-yl)pentan-l-one

[0493] A mixture of 47 (83 mg, 0.25 mmol) 101 (78 mg, 0.3 mmol), Pd₂(dba)₃ (27 mg, 0.03 mmol), and (2-biphenyl)dicyclohexyl phosphine (21 mg, 0.06 mmol) in Dioxane-DMF (3 ml; 8:2 v/v) was irradiated with microwave at 160 ⁰C for 45 min. The crude reaction mixture was purified using preparative HPLC. The desired fractions were combined, triturated with dichloromethane and aqueous saturated NaHCO₃. The organic layer was separated, dried (Na₂SO₄) and concentrated to give the title compound as a yellow solid (20 mg, 15%).

[0494] ¹H NMR (500 MHz, DMSO-J₆): δ 0.94 (t, J = 8.5 Hz, 3H), 1.35-1.45 (m, 2H), 1.62- 1.72 (m, 2H), 2.25 (s, 3H), 3.12 (t, J = 7.0 Hz, 2H), 3.19 (t, J = 4.2 Hz, 4H), 6.51 (dd, J = 8.0, 2.0 Hz, IH), 7.00-7.07 (m, IH), 8.50 (t, J= 8.5 Hz, IH), 7.35 (dd, J= 8.0, 1.0 Hz, IH), 7.41- 7.48 (m, IH), 7.65 (br s, IH), 8.02 (dd, J = 10.0, 2.0 Hz, IH), 8.15 (d, J = 8.8 Hz, IH), 8.63 (s, IH), 8.67 (s, IH), 9.18 (s, IH), 11.79 (s, IH)

MS (ES+): m/z 526 (M+H)⁺

Example 188 Preparation of 4-(6-(lH-Tetrazol-5-yl)benzo[b]thiophen-2-yl)-iV-(4-(2- (pyrrolidin-l-yl)ethoxy)phenyl)-7H-pyrrolo[2,3-(i]pyrimidin-2-amine

[0495] To a mixture of 2-{2-[4-(2-Pyrrolidin-l-yl-ethoxy)-phenylamino]-7H-pyrrolo[2,3- d]pyrimidin-4-yl}-benzo[b]thiophene-6-carbonitrile (48 mg, 0.1 mmol), sodium azide (71 mg, 1.1 mmol) and ZnBr₂ (247 mg, 1.1 mmol) in DMF-Η2O (3 mL, 8:2 v/v) was irradiated with microwave at 160 ⁰C for 45 min. The reaction mixture showed about half of the starting material left. More of sodium azide (71 mg, 1.1 mmol) and ZnBr₂ (247 mg, 1.1 mmol) were added and the reaction run for another 45 min under microwave conditions at 160 ⁰C. The crude reaction mixture was purified using preparative HPLC. The desired fractions were combined, triturated with dichloromethane and aqueous saturated NaHCO₃. The organic layer was separated, dried (Na₂SO₄) and concentrated to give the title compound as a orange solid (36 mg, 70%).

[0496] ¹H NMR (500 MHz, DMSO-J₆): δ 1.84-1.95 (m, 2H), 1.95-2.10 (m, 2H), 3.05-3.17 (m, 2H), 3.55-3.65 (m, 4H, superimposed with water peak), 4.36 (t, J = 4.5 Hz, 2H), 7.00 (d, J = 9.0 Hz, IH), 7.05-7.10 (m, IH), 7.38-7.45 (m, IH), 7.84 (d, J = 9.0 Hz, 2H), 8.15-8.25 (m, 2H), 8.58 (s, IH), 8.84 (s, IH), 9.24 (s, IH), 11.00-11.20 (m, IH), 11.78 (s, IH)

MS (ES+): m/z 524 (M+H)⁺

Example 189 Preparation of 2-(2-(4-(2-(Pyrrolidin-l-yl)ethoxy)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)benzo[b]thiophene-5-carbonitrile

[0497] A mixture of 7 (83 mg, 0.25 mmol), 75 (61 mg, 0.3 mmol), Pd₂(dba)₃ (27 mg, 0.03 mmol), and (2-biphenyl)dicyclohexyl phosphine (21 mg, 0.06 mmol) in Dioxane-DMF (3 ml; 8:2 v/v) was irradiated with microwave at 160 ⁰C for 45 min. The crude reaction mixture was purified using preparative ΗPLC. The desired fractions were combined, triturated with dichloromethane and aqueous saturated NaHCO₃. The organic layer was separated, dried (Na₂SO₄) and concentrated to give the title compound as a dark brown solid (12 mg, 10%). [0498] ¹H NMR (500 MHz, DMSO- J₆): δ 1.65- 1.75 (m, 4H), 2.54-2.60 (m, 4H), 2.78 (t, J = 6.0 Hz, 2H), 4.04 (t, J = 6.0 Hz, 2H), 6.90 (dd, J = 7.2, 2.2 Hz, 2H), 6.95-7.03 (m, IH), 7.35- 7.45 (m, IH), 7.76 (d, J = 6.5 Hz, 2H), 7.81 (dd, J = 9.0, 1.5 Hz, IH), 8.30 (d, J= 8.5 Hz, IH), 8.47 (d, J= 1.3 Hz, IH), 8.55 (s, IH), 9.17 (s, IH), 11.74 (s, IH)

MS (ES+): m/z 481 (M+H)⁺

Example 190 Preparation of l-(2-(2-(4-(2-(Pyrrolidin-l-yl)ethoxy)phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)benzo[b]thiophen-5-yl)pentan-l-one

[0499] A mixture of 7 (83 mg, 0.25 mmol) 101 (78 mg, 0.3 mmol), Pd₂(dba)₃ (27 mg, 0.03 mmol), and (2-biphenyl)dicyclohexyl phosphine (21 mg, 0.06 mmol) in Dioxane-DMF (3 ml; 8:2 v/v) was irradiated with microwave at 160 ⁰C for 45 min. The crude reaction mixture was purified using preparative ΗPLC. The desired fractions were combined, triturated with dichloromethane and aqueous saturated NaHCO₃. The organic layer was separated, dried (Na₂SO₄) and concentrated to give the title compound as a yellow solid (13 mg, 10 %).

[0500] ¹H NMR (500 MHz, DMSO-J₆): δ 0.93 (t, J= 8.5 Hz, 3H), 1.35-1.45 (m, 2H), 1.62- 1.72 (m, 6H), 2.54-2.60 (m, 4H), 2.78 (t, J= 6.0 Hz, 2H), 3.13 (t, J= 7.0 Hz, 2H), 4.04 (t, J = 6.0 Hz, 2H), 6.90 (dd, J = 9.5, 1.9 Hz, 2H), 6.96-7.05 (m, IH), 7.35-7.45 (m, IH), 7.77 (dd, J = 10.0, 2.0 Hz, 2H), 7.99 (dd, J= 8.5, 2.0 Hz, IH), 8.17 (d, J = 8.5 Hz, IH), 8.61 (s, IH), 8.66 (s, IH), 9.14 (s, IH), 11.70 (s, IH)

MS (ES+): m/z 541 (M+H)⁺ Example 191 Preparation of 5-(2-(3-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylthiophene-2-carbonitrile

[0501] A mixture of 47 (93 mg, 0.27 mmol), 53 (50 mg, 0.3 mmol), Pd₂(dba)₃ (27 mg, 0.03 mmol), and (2-biphenyl)dicyclohexyl phosphine (21 mg, 0.06 mmol) in Dioxane-DMF (3 ml; 8:2 v/v) was irradiated with microwave at 160 ⁰C for 45 min. The crude reaction mixture was purified using preparative ΗPLC. The desired fractions were combined, triturated with dichloromethane and aqueous saturated NaHCO₃. The organic layer was separated, dried (Na₂SO₄) and concentrated to give the title compound as a yellow solid (42 mg, 32 %).

[0502] ¹H NMR (500 MHz, DMSO-J₆): δ 2.23 (s, 3H), 2.43-2.50 (m, 4H superimposed with DMSO), 3.16 (t, J = 5.0 Hz, 4H), 6.50 (dd, J = 8.0, 2.0 Hz, IH), 6.94-6.97 (m, IH), 7.11 (t, J = 8.5 Hz, IH), 7.22 (dd, J = 8.0, 1.1 Hz, IH), 7.40-7.47 (m, IH), 7.64-7.67 (m, IH), 8.15 (s, IH), 9.18 (s, IH), 11.78 (s, IH)

MS (ES+): m/z 430 (M+H)⁺

Example 192 Preparation of 4-(4-Methylthiophen-2-yl)-N-(4-moφholin-4-ylphenyl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine

[0503] Argon was bubbled through a solution of 9 (100 mg, 0.25 mmol), 4- morpholinobenzenamine (53 mg, 0.3 mmol), palladium acetate (5.6 mg, 0.025 mmol), tris-tert- butylphosphine (10 mg, 0.05 mmol), triethylamine (252 mg, 2.5 mmol), in dimethyl formamide (2 niL) for 5 min. The solution was heated in a microwave at 150 ⁰C for 30 min. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, filtered through a silica plug, concentrated, dissolved in dimethyl formamide (2 mL) and stirred with and treated with tetrabutyl ammonium fluoride (653 mg, 2.5 mmol) in tetrahydrofuran at 60 ⁰C for 30 min. The solution was concentrated and purified on preparative high performance liquid chromatography to give the title compound as a light brown solid (29 mg, 30%).

[0504] ¹H NMR (500 MHz, DMSO-J₆): δ 2.32 (s, 3H), 3.02-3.04 (m, 4H), 3.72-3.76 (m, 4H), 6.82 (dd, J = 3.6, 1.7 Hz, IH), 6.90 (d, J = 9.0 Hz, 2H), 7.23-7.25 (m, IH), 7.37 (d, J = 1 Hz, IH), 7.74 (d, / = 9.1 Hz, 2H), 7.89 (d, J = 0.8 Hz, IH), 8.95 (s, IH), 11.54 (s, IH)

MS (ES+): m/z 392 (M+H)⁺

Example 193 Preparation of N-(4-(2-(Dimethylamino)ethoxy)phenyl)-4-(4-methylthiophen-2- yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine

[0505] The title compound was prepared as described above from 9 (100 mg, 0.25 mmol) and 4-(2-(dimethylamino)ethoxy)benzenamine (54 mg, 0.3 mmol) to give a yellow solid (27 mg, 28%).

[0506] ¹H NMR (500 MHz, DMSO-J₆): δ 2.29 (s, 6H), 2.32 (s, 3H), 2.65-2.75 (m, 2H), 4.04 (t, J = 5.8 Hz, 2H), 6.83 (dd, J = 3.6, 1.6, IH), 6.88 (d, J= 9.0 Hz, 2H), 7.25 (dd, J= 3.5, 2.4 Hz, IH), 7.37 (t, J = 1.2 Hz, IH), 7.77 (d, J = 9.1 Hz, 2H), 7.89 (d, J = 0.9 Hz, IH), 8.99 (s, IH), 11.55 (s, IH)

MS (ES+): m/z 394 (M+H)⁺

Example 194 Preparation of 4-(4-Methylthiophen-2-yl)-N-[4-(l,3-oxazol-5-yl)phenyl]-7H- pyrrolo[2,3-d]pyrimidin-2-amine

[0507] The title compound was prepared as described above from 9 (100 mg, 0.25 mmol) and 4-(oxazol-5-yl)benzenamine (48 mg, 0.3 mmol) to give a yellow solid (42 mg, 45%).

[0508] ¹H NMR (500 MHz, DMSO-J₆): δ 2.33 (s, 3H), 6.89 (dd, J = 3.6, 1.6 Hz, IH), 7.33 (dd, J = 3.5, 2.4 Hz, IH), 7.41 (t, J= 1.2 Hz, IH), 7.54 (s, IH), 7.64 (d, J = 8.8 Hz, 2H), 7.94 (d, J = 0.7, IH), 8.03 (d, J= 8.8 Hz, 2H), 8.36 (s, IH), 9.49 (s, IH), 11.70 (s, IH)

MS (ES+): m/z 374 (M+H)⁺

Example 195 Preparation of N-{4-[2-(lH-Benzimidazol-2-yl)ethyl]phenyl}-4-(4- methylthiophen-2-yl)-7H-pyrrolo[2,3-J]pyrimidin-2-amine

[0509] The title compound was prepared as described above from 9 (100 mg, 0.25 mmol) and 4-(2-(lH-benzo[d]imidazol-2-yl)ethyl)benzenamine (71 mg, 0.3 mmol) to give a yellow solid (27 mg, 24%).

[0510] ¹H NMR (500 MHz, DMSO-J₆): δ 2.32 (s, 3H), 3.04-3.12 (m 4H), 6.84 (dd, J = 3.3, 1.4 Hz, IH), 7.11 (dd, J = 5.9, 2.9 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H), 7.27 (t, J = 3.2 Hz, IH), 7.38 (s, IH), 7.44 (br s, IH), 7.50 (br s, IH), 7.78 (d, J = 8.5 Hz, 2H), 7.90 (s, IH), 9.11 (s, IH), 11.59 (s, IH), 12.20 (s, IH)

MS (ES+): m/z 451 (M+H)⁺ Example 196 Preparation of 4-(4-Methylthiophen-2-yl)-Λf-[4-(2-morpholin-4- ylethoxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-2-amine

[0511] The title compound was prepared as described above from 9 (100 mg, 0.25 mmol) and 4-(2-morpholinoethoxy)benzenamine (66 mg, 0.3 mmol) to give a yellow solid (32 mg, 29%).

[0512] ¹H NMR (500 MHz, DMSO- J₆): δ 2.32 (s, 3H), 2.47-2.49 (m, 4H), 2.68 (t, J = 5.8 Hz, 2H), 3.58 (t, J = 4.5 Hz, 4H), 4.05 (t, J = 5.8 Hz, 2H), 6.82 (dd, J = 3.4, 1.5 Hz, IH), 6.87 (d, J = 9.0 Hz, 2H), 7.24 (t, J = 3.2 Hz, IH), 7.37 (s, IH), 7.76 (d, / = 9.1 Hz, 2H), 7.89 (s, IH), 8.99 (s, IH), 11.55 (s, IH)

MS (ES+): m/z 436 (M+H)⁺

Example 197 Preparation of jV-{4-[2-(4-Methylpiperazin-l-yl)ethoxy]phenyl}-4-(4- methylthiophen-2-yl)-7H-pyrrolo[2,3-J]pyrimidin-2-amine

[0513] The title compound was prepared as described above from 9 (100 mg, 0.25 mmol) and 4-(2-(4-methylpiperazin-l-yl)ethoxy)benzenamine (71 mg, 0.3 mmol) to give a yellow solid (27 mg, 24%). [0514] ¹H NMR (500 MHz, DMSO-J₆): δ 2.17 (s, 3H), 2.32 (s, 3H), 2.33-2.50 (m, 8H), 2.67 (t, J = 5.8 Hz, 2H), 4.03 (t, J = 5.9 Hz, 2H), 6.82 (dd, J= 3.6, 1.8 Hz, IH), 6.87 (d, J = 9.0 Hz, 2H), 7.24 (dd, J= 3.4, 2.4 Hz, IH), 7.37 (s, IH), 7.76 (d, J = 9.0 Hz, 2H), 7.89 (s, IH), 8.99 (s, IH), 11.55 (s, IH)

MS (ES+): m/z 449 (M+H)⁺

Example 198 Preparation of Λ^{4-[(l-Methylpiperidin-4-yl)oxy]phenyl}-4-(4-methylthiophen- 2-yl)-7H-pyrrolo[2,3-J]pyrimidin-2-amine

[0515] The title compound was prepared as described above from 9 (100 mg, 0.25 mmol) and 4-(l-methylpiperidin-4-yloxy)benzenamine (62 mg, 0.3 mmol) to give a yellow solid (27 mg, 26%).

[0516] ¹H NMR (500 MHz, DMSO-J₆): δ 1.67 (br s, 2H), 1.93 (br s, 2H), 2.29 (br s, 3H), 2.32 (s, 3H), 2.36 (br s, 2H), 2.74 (br s, 2H), 4.30 (br s, IH), 6.83 (dd, J = 3.6, 1.6 Hz, IH), 6.89 (d, J = 9.0 Hz, 2H), 7.25 (dd, J = 3.4, 2.4 Hz, IH), 7.38 (s, IH), 7.76 (d, J = 9.0 Hz, 2H), 7.90 (s, IH), 9.00 (s, IH), 11.55 (s, IH)

MS (ES+): m/z 420 (M+H)⁺

Example 199 Preparation of Intermediate

102 3-(2-Pyrrolidin-l-yl-ethoxy)-phenylamine (102)

[0517] A mixture of l-[2-(3-bromo-phenoxy)-ethyl] -pyrrolidine (2.0 g, 7.4 mmol), acetamide (0.55 g, 9.3 mmol), Pd₂(dba)₃ (0.4 g, 0.44 mmol), Xantphos (0.5 g, 0.86 mmol) and cesium carbonate (4.5 g, 13.8 mmol) were suspended in dioxane (20 mL) and heated at reflux under the argon atmosphere for 2 h. The reaction mixture was cooled to room temperature, filtered and the filtered solid washed with DCM. The filtrate was concentrated in vacuo and the residue suspended in 25 mL of Claisen alkali. The mixture was heated at 70 ⁰C for 6 h and then poured into water and extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the crude product used in the next step without purification.

Example 200 Preparation of [4-(4-Methyl-thiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-[3- (2-pyrrolidin- 1 -yl-ethoxy)-phenyl] -amine

[0518] A mixture of 1 (0.20 g, 0.80 mmol), 102 (0.25 g, 1.2 mmol), Pd₂(dba)₃ (40 mg,

0.044 mmol), P(^-Bu)₃ (1 M in toluene; 0.1 mL, 0.1 mmol) and potassium ^-butoxide (0.45 g, 4.0 mmol) in a mixture of dioxane/DMF (1/1, 6 mL) was irradiated with microwave at 160 ⁰C for 30 min. After cooling to room temperature, the mixture was filtered, the filtered solid washed with DCM and the filtrate concentrated. The crude product was purified by ΗPLC, the fractions combined and poured into saturated NaHCO₃ solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a yellow solid (12 mg, 4%).

[0519] ¹H NMR (500 MHz, DMSO-J₆): δ 1.69-1.77 (m, 4H), 2.33 (s, 3H), 2.55-2.70 (m, 4H), 2.85-2.95 (m, 2H), 4.12 (t, J = 5.6 Hz, 2H), 6.48 (dd, J = 8.0, 2.1 Hz, IH), 6.86 (dd, J = 3.6, 1.8 Hz, IH), 7.15 (t, J= 8.2 Hz, IH), 7.31 (dd, J= 3.6, 2.3 Hz, IH), 7.35-7.41 (m, 2H), 7.69 (t, J = 2.1 Hz, IH), 7.92 (d, J = 0.8 Hz, IH), 9.19 (s, IH), 11.66 (s, IH)

MS (ES+): m/z 420 (M+H)⁺ Example 201: Enzyme Assays

[0520] The IC₅₀ values for compounds were determined using a luminescence -based kinase assay with recombinant JAK2, JAK3 and KDR (VEGF_r2) obtained from Invitrogen. In white, flat-bottom, 96-well plates (Nunc) parallel assays were run at room temperature at a final volume of 50 μL. Each well contained 40 μL of buffer consisting of: 40 mM Tris buffer, pH 7.4, containing 50 mM MgCl₂, 800 μM EGTA, 350 μM Triton X-100, 2 mM β- mercaptoethanol, 250 μM peptide substrate and an appropriate amount of either JAK2, JAK3 or KDR (75 - 25 ng/well) such that the assay was linear over 60 min. The final concentrations of compounds for IC₅₀ value determinations ranged from 10 to 0.001 μM by adding the appropriate amount of compound in 2.5 μL of DMSO; the DMSO present in each assay was constant at 5%. The reaction was initiated by the addition of 10 μL of ATP to a final assay concentration of 3 μM. After the reaction had proceeded for 60 min, 50 μL of Kinase-Glo reagent (Promega) was added to terminate the reaction. This solution was then allowed to proceed for an additional 10 min to maximize the luminescence reaction. Values were then measured using an Ultra 384 instrument (Tecan) set for luminosity measurements. Two control reactions were also run: one reaction containing no compound and the second containing neither inhibitor nor peptide substrate. IC₅₀ values were derived from experimental data using the non-linear curve fitting capabilities of Prism (Version 4; GraphPad Software). The results, expressed as IC₅₀, are presented in Table 1.

Example 202 Cell Proliferation Assay

[0521] The EC₅₀ values for compounds were determined using a colormetric-based cell profileration assay. In clear, flat-bottom, 96-well plates parallel assays were run at 37 ⁰C and 6.5% CO₂ at a final volume of 100 μL. Each well contained 99 μL of RPMI medium containing 10% inactivated fetal calf serum, 2 mM L-glutamine, 1 mM sodium pyruvate, non- essential amino acids and an appropriate amount of human erythroleukemia (HEL) cells that are driven by the V617F mutation of JAK2 and varying amounts of compound in DMSO. The final concentrations of compounds for EC₅₀ value determinations ranged from 10 to 0.001 μM by adding the appropriate amount of compound in 1 μL of DMSO; the DMSO present in each assay was constant at 1%. The cells were allowed to proliferate in the presence of the inhibitor for approximately 72 h, XTT (3'-[l-(phenylamino-carbonyl)-3,4-tetrazolium]-bis(4-methoxy- 6-nitro)benzene sulfonic acid) was added to a final concentration of 0.3 mg/niL. After the mixture was allowed to proceed for an additional 6 h, the absorbance values at 492 nm were measured to assess the formation of the formazan product. The absorbance at 690 nm was also measured for subtraction of turbidity values. EC₅₀ values were derived from experimental data using the non-linear curve fitting capabilities of Prism (Version 4; GraphPad Software). Table 1. Data for compounds in nM

EXAMPLE 203 TYK2 Enzyme Inhibition Study

[0522] Inhibition of TYK2 by compounds of the invention was assessed using the Invitrogen single point method. The single point TYK2 inhibition data were obtained at a 250 nM concentration of test compound. A higher percent inhibition indicates a more potent compound in this assay. Each data point is the mean of two independent determinations. Inhibition levels of greater than >80% indicate virtually complete inhibition within the limits of experimental determination. For some compounds, IC₅₀ values were also determined. The results are given in Table 2.

Table 2: Data for selected compounds against TYK2

Example 204 Pharmokinetic Data

[0523] Pharmacokinetic (PK) protocol: Male Balb/c mice were used, n=24 for intravenous (IV), n=18 for oral (PO) with 3 animals/timepoint. Intravenous and oral dose formulations were prepared as needed. Dose was as follows: IV = 5 mg/kg, PO = 25 mg/kg. The time points for blood collection were:

For IV: 5, 15, 30 min, 1, 2, 4, 6, and 24 hr post dose (n=3 for each time-point);

PO: 30 min, 1, 2, 4, 6, and 24 hr post dose (n=3 for each time -point).

[0524] The PK evaluation in rats utilized the same procedures described above except the number of rats was three per time point per dosed group and the blood samples were collected by cardiac puncture. Blood was maintained in an ice and water mixture prior to centrifugation to obtain plasma. Plasma samples are transferred to a -2O⁰C freezer and stored until analysis. [0525] Matrix calibration standards and QC samples were prepared by spiking the compound into blank mouse plasma. The final concentrations of a selected compound were 0, 1, 5, 10, 50, 100, 500, 1000, 2500 and 5000 ng/niL for calibration standards, and 2.50, 25.0, 250 and 2500 for QC samples.

[0526] Plasma samples were processed using a standard protocol. The samples were analyzed using a LC/MS/MS Waters Quattro LC by standard determined conditions. Chromatogram signals were integrated and calibrated using MassLynx 3.0. Pharmacokinetic parameters were estimated using WinNonlin (version 4.1) from mean plasma concentration- time profiles. The values for the maximum plasma concentration (C_max) and the time to maximum concentration (T_max) were determined from measured plasma concentrations. The area under the curves, AUC ₍i_ast) and AUC _(inf) were calculated from plasma concentration-time profiles using the linear trapezoidal rule. The oral bioavailability (F) was calculated using the following equation; F = (AUC(o-_mf),po x Div)/(AUC(o-_mf),iv x Dpo)*100%.

[0527] Results of pharmokinetic study with mice is shown in Table 3.

Table 3.

Table 4 shows results of pharmacokinetic studies in rats, as described above.

Table 4.

[0528] As described above, mice were dosed orally (PO) with 25 mg/kg compound, and the plasma concentration at 1 and 4 hours was measured in triplicate. The results are given in Tables 5 and 6.

Table 5: Plasma concentrations of compound 1 hour after dosing

Table 6: Plasma concentrations of compound 4 hours after dosing

References

[0529] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

Equivalents

[0530] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations. [0531] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention.

Claims

Claims

1. A compound represented by formula I:

wherein

R₁ is a heteroaryl containing at least one S atom, and optionally substituted on a ring carbon by one, two, or three substituents each independently selected from the group consisting of: halo, hydroxyl, nitro, formyl, formamido, cyano, sulfonyl, carboxy, amino, amido, acylamino, carbamoyl, sulphamoyl, alkyl, alkenyl, CF₃, ureido, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, carbaldehyde oxime, N-alkylsulphamoyl, N- alkylcarbamoyl, -OR₁₃R₁₁ or -R₁₃R₁₁;

R₂ is phenyl or pyridinyl, wherein R₂ is optionally substituted on a ring carbon by one, two, or three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, nitro, formyl, formamido, carboxy, sulfonyl, amino, amido, -N-alkyl-amino, carbamoyl, sulphamoyl, CF₃, ureido, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, N-alkylcarbamoyl, -OR₁₁, -OR₁₂R₁₁, or -R₁₂R₁₁;

Rn is independently selected from the group consisting of: aryl, heteroaryl, cycloalkyl and heterocycloalkyl, wherein R₁₁ can be optionally substituted by one to four substituents each independently selected from the group consisting of: halo, alkyl, carbonyl, hydroxyl, alkyl-hydroxyl, nitro, formyl, formamido, carboxy, amino, amido, CF₃, ureido, carbamoyl, sulphamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, N-alkylcarbamoyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl;

R₁₂ is alkylene, -SO₂-, -C(O)-, -SO₂N-alkylene-, or a bond; R₁₃ is alkylene, alkenylene, -C(O)-, -SO₂-, or a bond; or

pharmaceutically acceptable salts and N-oxides thereof.

2. The compound of claim 1, wherein R₁ is an optionally substituted monocyclic or bicyclic heteroaryl.

3. The compound of claim 1 or 2, wherein R₁ is optionally substituted thiophene, or optionally substituted benzothiophene.

4. The compound of any of claims 1-3, wherein a substituent of R₁ at the ortho position relative to the pyrrolopyrimidine is H.

5. The compound of any one of claims 1-3, wherein R₁ is represented by:

wherein R₃ and R₄ are each independently selected from the group consisting of: hydrogen, halo, hydroxyl, cyano, nitro, formyl, formamido, carboxy, amino, amido, acylamino, sulfonyl, carbamoyl, sulphamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, N-alkylcarbamoyl, aryl, heterocycle, cycloalkyl, -OR₁₃R₁₁, or -R₁₃R₁₁, or R₃ and R₄ taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic or heterocyclic ring, optionally substituted by one to four substituents each independently selected from the group consisting of: halo, cyano, alkyl, carbonyl, hydroxyl, nitro, formyl, formamido, carboxy, amino, carbamoyl, sulphamoyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, and N- alkylcarbamoyl.

6. The compound of any one of claims 1-5, wherein R₁ is selected from:

wherein for each occurrence, R₅ is independently selected from the group consisting of: H, halo, cyano, acylamino, alkanoyl, carbaldehyde oxime, and alkyl.

7. The compound of claim any one of claims 1-6, wherein R₅ is independently selected, for each occurrence, from H, methyl, ethyl, or propyl, wherein said methyl, ethyl, or propyl may be optionally substituted by halo, hydroxyl, or cyano.

8. The compound of any one of claims 1-7, wherein R₂ is

wherein:

X is N or CR₆; R₆ is H or alkyl;

R₇ and Rg, independently for each occurrence, is chosen from the group consisting of: H, heterocycle, -O-heterocycle, -alkylene-heterocycle, -O-alkylene-heterocycle, -SO₂N- alkylene-heterocycle, or -SO₂-heterocycle, wherein said heterocycle for each occurrence is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, alkyl, carbonyl, hydroxyl, nitro, formyl, formamido, carboxy, amino, amido, carbamoyl, sulphamoyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N- alkylsulphamoyl, and N-alkylcarbamoyl.

9. The compound of claim 8, wherein said heterocycle is substituted with methyl.

10. The compound of claim 9, wherein Rg is H and R₇ is a heterocycle or -O-alkylene- heterocycle, wherein said heterocycle is chosen from the group consisting of: pyrrolidinyl, piperazinyl, imidazoyl, piperdinyl, and morpholinyl.

11. The compound of claim 10, wherein Rg is H and R₇ is selected from the group consisting of: -CH₂-piperdine, -CH₂- methylimidazole, methylpiperazine, piperazine, -CH₂-morpholine, amidozole, -CH₂-pyrrolidine, and 2-pyrrolidin-lyl-ethoxy.

12. The compound of claim 7, wherein Rg is H.

13. The compound of any one of claims 7-12, wherein X is N.

14. The compound of any one of claims 7-13, wherein X is CR₆.

15. The compound of any one of claims 5-14, wherein at least one R₅ is methyl.

16. A compound represented by formula II:

II

wherein:

R₃ and R₄ are each independently selected from the group consisting of: hydrogen, halo, cyano, sulfonyl, hydroxyl, nitro, formyl, formamido, carboxy, amino, amido, acylamino, carbaldehyde oxime, carbamoyl, sulphamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, N-alkylcarbamoyl, or -R₁₃R₁₁, or R₃ and R₄ taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic or heterocyclic ring, optionally substituted by one to four substituents each independently selected from the group consisting of: halo, alkyl, carbonyl, hydroxyl, nitro, formyl, formamido, carboxy, amino, amido, carbamoyl, sulphamoyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, N-alkylcarbamoyl or -R₁₃R₁₁;

X is N or CR₆;

R₆ is H or alkyl;

R₇ and R₈ are each independently selected from the group consisting of: H, heterocycle, -O-alkyl, -O-heterocycle, -O-alkylene -heterocycle, -SChN-heterocycle, -SCh-heterocycle, - C(O)-heterocycle, -C(O)-NH-alkyl-C(O)OH, -alkylene-heterocycle, or -N- alkylene- amino, wherein said heterocycle is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, alkyl, carbonyl, hydroxyl, nitro, formyl, formamido, carboxy, amino, amido, carbamoyl, sulphamoyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, and N-alkylcarbamoyl, wherein Rg is H;

R₁₁ is independently selected from the group consisting of: aryl, heteroaryl, cycloalkyl and heterocycloalkyl, wherein R₁₁ can be optionally substituted by one to four substituents each independently selected from the group consisting of: halo, alkyl, carbonyl, hydroxyl, nitro, oxo, formyl, formamido, carboxy, amino, amido, carbamoyl, sulphamoyl, alkyl, alkenyl, sulfonyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N- alkylsulphamoyl, N-alkylcarbamoyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl;

R₁₃ is alkylene, alkenylene, -C(O)-, -SO₂-, or a bond;

or pharmaceutically acceptable salts and N-oxides thereof.

17. The compound of claim 16, wherein R₃ and R₄ are each independently selected from the group consisting of: H, methyl, and ethyl.

18. The compound of claims 16 or 17, wherein said heterocycle is chosen from the group consisting of: pyrrolidinyl, piperazinyl, morpholinyl, piperdine, pyridinyl, imidazoyl, and triazoyl.

19. The compound of claim 16, wherein the compound is represented by:

Ilia or IHb

wherein R₉, independently for each occurrence, is chosen from the group consisting of: H, cyano, methyl, ethyl, -C(O)-alkyl -C(O)-heterocycle, or -heterocycle;

R₁₉, independently for each occurrence, is chosen from H or halo; and

R_9a is chosen from the group consisting of: H, alkyl, amido, -N-alkyl-sulfamoyl, sulfonyl, alkanoyl, carbamoyl, -C(0)-alkyl-NR₂oR2o, -C(O)-heterocycle, and heterocycle, wherein R₂o is independently selected from H and alkyl.

20. The compound of claim 19, wherein Rg_a is -C(O)-N-R₂OR₂O

21. The compound of any one of claims 16-20, wherein R₃ is H or methyl and R₄ is H or methyl.

22. The compound of any one of claims 16-21, wherein R₇ or R₈ is selected from the group consisting of:

and , wherein R_1S is alkyl or alkanoyl.

23. The compound of any one of claims 16-22, wherein R₃ or R₄ is selected from the group consisting of:

, wherein R₁₆ is chosen from the group consisting of: H, alkyl, alkoxy, halo, -SOi-heterocycle, and N-alkyl sulphamoyl.

24. The compound of any one of claims 15-22, wherein R₃ is H or R₄ is H.

25. The compound of claim 18, wherein Rg_a is chosen from the group consisting of:

and

26. A compound selected from the group consisting of:

N-(4-(4-methylpiperazin-l-yl)phenyl)-4-(4-methylthiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin- 2-amine,

4-[4-(4-Methyl-thiophen-2-yl)-7H-pyrrolo[2,3-J]pyrimidin-2-ylamino]-N-(2-pyrrolidin-l-yl- ethyl)-benzenesulfonamide, [4-(4-Methyl-piperazin-l-yl)-phenyl]-[4-(5-methyl-thiophen-2-yl)-7H-pyrrolo[2,3- J]pyrimidin-2-yl] -amine,

[4-(5-Chloro-thiophen-2-yl)-7H-pyrrolo[2,3-J]pyrimidin-2-yl]-[4-(2-pyrrolidin-l-yl-ethoxy)- phenyl] -amine,

(5-{2-[4-(2-Pyrrolidin-l-yl-ethoxy)-phenylamino]-7H-pyrrolo[2,3-(i]pyrimidin-4-yl}- thiophen-2-yl)-methanol,

4-(4-Methylthiophen-2-yl)-N-(4-(pyridin-4-ylmethyl)phenyl)-7H-pyrrolo[2,3-J]pyrimidin-2- amine,

N-(4-((lH-l,2,4-Triazol-l-yl)methyl)phenyl)-4-(4-methylthiophen-2-yl)-7H-pyrrolo[2,3- J]pyrimidin-2-amine,

4-(4-Methylthiophen-2-yl)-N-(4-(pyridin-3-yl)phenyl)-7H-pyrrolo[2,3-J]pyrimidin-2-amine,

4-(4-Methylthiophen-2-yl)-N-(4-(piperidin-4-yloxy)phenyl)-7H-pyrrolo[2,3-J]pyrimidin-2- amine,

4-(4-Methylthiophen-2-yl)-N-(4-(piperidin-l-ylmethyl)phenyl)-7H-pyrrolo[2,3-(i]pyrimidin-2- amine,

(5-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-J]pyrimidin-4-yl)thiophen-2- yl)methanol,

5-(2-(4-Morpholinophenylamino)-7H-pyrrolo[2,3-(i]pyrimidin-4-yl)thiophene-2-carboxamide,

[4-(5-Methyl-thiophen-2-yl)-7H-pyrrolo[2,3-J]pyrimidin-2-yl]-[4-(piperidine-4-sulfonyl)- phenyl] -amine,

[4-(4-Methyl-thiophen-2-yl)-7H-pyrrolo[2,3-J]pyrimidin-2-yl]-(3-pyrrolidin-l-ylmethyl- phenyl)-amine,

[4-(4-Methyl-thiophen-2-yl)-7H-pyrrolo[2,3-J]pyrimidin-2-yl]-(3-morpholin-4-ylmethyl- phenyl)-amine, 4-(4-Methylthiophen-2-yl)-N-[4-(moφholin-4-ylmethyl)phenyl]-7H-pyrrolo[2,3-^]pyrimidin- 2-amine,

N- { 4- [(2-Methyl- lH-imidazol- 1 -yl)methyl]phenyl } -4-(4-methylthiophen-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine,

4-(4-Methylthiophen-2-yl)-N-[4-(2-morpholin-4-ylethyl)phenyl]-7H-pyrrolo[2,3-rf]pyrimidin- 2-amine,

N-(6-(4-Methylpiperazin-l-yl)pyridin-3-yl)-4-(4-methylthiophen-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-amine,

N-[4-(lH-Imidazol-l-yl)phenyl]-4-(4-methylthiophen-2-yl)-7H-pyrrolo[2,3-J]pyrimidin-2- amine,

N-(4-Methoxyphenyl)-4-(thiophen-2-yl)-7H-pyrrolo[2,3-(i]pyrimidin-2-amine,

N-(4-(2-(Pyrrolidin-l-yl)ethoxy)phenyl)-4-(thiophen-2-yl)-7H-pyrrolo[2,3-J]pyrimidin-2- amine,

N-(3-Morpholinopropyl)-4-(thiophen-2-yl)-7H-pyrrolo[2,3-(i]pyrimidin-2-amine,

2-(4-Methoxyphenoxy)-4-(thiophen-2-yl)-7H-pyrrolo[2,3-J]pyrimidine,

5-(5-{2-[4-(2-Pyrrolidin-l-yl-ethoxy)-phenylamino]-7H-pyrrolo[2,3-J]pyrimidin-4-yl}- thiophen-2-ylmethylene)-thiazolidine-2,4-dione,

(Z)-5-((5-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-J]pyrimidin-4- yl)thiophen-2-yl)methylene)thiazolidine-2,4-dione,

5-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-(i]pyrimidin-4-yl)thiophene-2- carbonitrile,

(5-(2-(4-(4-methylpiperazin- l-yl)phenylamino)-7Η-pyrrolo[2,3-d]pyrimidin-4-yl)thiophen-2- yl)(morpholino)methanone, [4-(5-Methyl-benzo[b]thiophen-2-yl)-7H-pyrrolo[2,3-^]pyrimidin-2-yl]-[4-(2-pyrrolidin-l-yl- ethoxy) -phenyl] -amine,

[4-(5-Methyl-benzo[b]thiophen-2-yl)-7H-pyrrolo[2,3-J]pyrimidin-2-yl]-[4-(4-methyl- piperazin- 1 -ylmethyl)-phenyl] -amine,

4-(Benzo[b]thiophen-2-yl)-N-(4-(4-methylpiperazin-l-yl)phenyl)-7H-pyrrolo[2,3-(i]pyrimidin- 2-amine,

4-(Benzo[b]thiophen-2-yl)-N-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)-7H-pyrrolo-[2,3- d]pyrimidin-2-amine,

N-(4-(2-(Pyrrolidin-l-yl)ethoxy)phenyl)-4-(benzo[b]thiophen-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-amine, or pharmaceutically acceptable salts and N-oxides thereof.

27. A compound selected from the group consisting of:

or pharmaceutically acceptable salts and N-oxides thereof.

28. A compound selected from the group consisting of:

[4-(4-Methyl-thiophen-2-yl)-7H-pyrrolo[2,3-(i]pyrimidin-2-yl]-[4-(2-pyrrolidin-l-yl-ethoxy)- phenyl] -amine; [4-(5-Methyl-thiophen-2-yl)-7H-pyrrolo[2,3-^]pyrimidin-2-yl]-[4-(2-pyrrolidin-l-yl-ethoxy)- phenyl] -amine;

{4-[5-(3,5-Dimethyl-isoxazol-4-yl)-thiophen-2-yl]-7H-pyrrolo[2,3-J]pyrimidin-2-yl}-[4-(2- pyrrolidin- 1 -yl-ethoxy)-phenyl] -amine;

2-{2-[4-(2-Pyrrolidin-l-yl-ethoxy)-phenylamino]-7H-pyrrolo[2,3-(i]pyrimidin-4-yl}- benzo[b]thiophene-6-carbonitrile;

{4-[5-(3,5-Dimethyl-isoxazol-4-yl)-thiophen-2-yl]-7H-pyrrolo[2,3-J]pyrimidin-2-yl}-[4-(2- methyl-imidazol- 1 -ylmethyl)-phenyl] -amine;

2- { 2- [4-(2-Methyl-imidazol- 1 -ylmethyl)-phenylamino] -7H-pyrrolo [2,3-<i]pyrimidin-4-yl } - benzo[b]thiophene-6-carbonitrile;

{4-[5-(3-Isopropoxy-phenyl)-thiophen-2-yl]-7H-pyrrolo[2,3-(i]pyrimidin-2-yl}-[4-(2- pyrrolidin- 1 -yl-ethoxy)-phenyl] -amine;

N-fer?-Butyl-3-(5-{2-[4-(2-methyl-imidazol-l-ylmethyl)-phenylamino]-7H-pyrrolo[2,3- d]pyrimidin-4-yl}-thiophen-2-yl)-benzenesulfonamide;

{4-[5-(2,3-Dihydro-benzo[l,4]dioxin-6-yl]-thiophen-2-yl]-7Η-pyrrolo[2,3-d]pyrimidin-2-yl}-4-(2- methyl-imidazol-imidazol- 1 -ylmethyl)-phenyl] -amine ;

{4-[5-(3-Isopropoxy-phenyl)-thiophen-2-yl]-7H-pyrrolo[2,3-J]pyrimidin-2-yl}-[4-(2-methyl- imidazol- 1 -ylmethyl)-phenyl] -amine;

(2-{2-[3-(4-Methyl-piperazin-l-yl)-phenylamino]-7Η-pyrrolo[2,3-d]pyrimidin-4-yl}- benzo[b]tmophen-5-yl)-moφholin-4-yl-methanone;

[3-(4-Methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-[4-(4-methyl-thiophen-2-yl)-7H- pyrrolo[2,3-_<i]pyrimidin-2-yl]-amine;

4-(4-Methylthiophen-2-yl)-N-(4-(l-moφholinoethyl)phenyl)-7H-pyrrolo[2,3-<i]pyrimidin-2- amine hydrochloride; N-(4-(2-Methyl- lΗ-imidazol- l-yl)phenyl)-4-(4-methylthiophen-2-yl)-7Η-pyrrolo[2,3- d]pyrimidin-2- amine hydrochloride; 2-(4-(4-(4-Methylthiophen-2-yl)-7H-pyrrolo[2,3-(i]pyrimidin-2-ylamino)benzamido)acetic acid; 4-(4-Methylthiophen-2-yl)-N-(4-(pyrrolidin-l-ylmethyl)phenyl)-7H-pyrrolo[2,3-^]pyrimidin- 2- amine; 5-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-^]pyrimidin-4-yl)thiophene-2- carboxamide;

2-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-^]pyrimidin-4- yl)benzo[b]thiophene-7-carbonitrile;

2-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)benzo[b]thiophene-4-carbonitrile;

5-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-^]pyrimidin-4-yl)-3- methylthiophene-2-carbonitrile;

5-(2-(4-(2-(Pyrrolidin-l-yl)ethoxy)phenylamino)-7H-pyrrolo[2,3-J]pyrimidin-4-yl)-3- methylthiophene-2-carbonitrile;

2-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-(i]pyrimidin-4-yl)thiophene-3- carbonitrile;

2-(2-(3-(4-Methylpiperazin-l-yl)phenylamino)-7Η-pyrrolo[2,3-d]pyrimidin-4-yl)thiophene-3- carbonitrile;

4-(5-(3,5-Dimethylisoxazol-4-yl)thiophen-2-yl)-N-(4-(moφholinomethyl)phenyl)-7H- pyrrolo[2,3-_<i]pyrimidin-2-amine;

4-(Benzo[b]thiophen-2-yl)-N-(4-(moφholinomethyl)phenyl)-7H-pyrrolo[2,3-<i]pyrimidin-2- amine hydrochloride;

2-(2-(4-(Moφholinomethyl)phenylamino)-7H-pyrrolo[2,3-^]pyrimidin-4- yl)benzo[b]thiophene-6-carbonitrile;

4-(5-Methylbenzo[b]thiophen-2-yl)-N-(4-(moφholinomethyl)phenyl)-7H-pyrrolo[2,3- d] pyrimidin-2- amine;

4-(Benzo[b]thiophen-2-yl)-N-(4-((piperidin-l-yl)methyl)phenyl)-7H-pyrrolo[2,3-^]pyrimidin- 2-amine; 4-(Benzo[b]thiophen-2-yl)-N-(4-((piperidin-l-yl)methyl)phenyl)-7H-pyrrolo[2,3-(i]pyrimidin- 2- amine;

N-fert-Butyl-5-(2-(4-((2-methyl-lH-imidazol-l-yl)methyl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)thiophene-2-carboxamide;

(4-Methylpiperazin-l-yl)(3-(4-(4-methylthiophen-2-yl)-7H-pyrrolo[2,3-(i]pyrimidin-2- ylamino)phenyl)methanone;

N-fer?-Butyl-3-methyl-5-(2-(4-(2-(pyrrolidin-l-yl)ethoxy)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)thiophene-2-carboxamide;

5-(2-(4-(lH-Imidazol-l-yl)phenylamino)-7H-pyrrolo[2,3-(i]pyrimidin-4-yl)thiophene-2- carbonitrile;

4-(4-Methylthiophen-2-yl)-N-(4-((piperazin-l-yl)methyl)phenyl)-7H-pyrrolo[2,3-(i]pyrimidin- 2-amine;

l-(4-((4-(4-(4-Methylthiophen-2-yl)-7H-pyrrolo[2,3-J]pyrimidin-2- ylamino)phenyl)methyl)piperazin- 1 -yl)ethanone;

2-Methyl-l-(4-{4-[4-(4-methyl-thiophen-2-yl)-7H-pyrrolo[2,3-J]pyrimidin-2-ylamino]- benzyl }-piperazin-l-yl)-propan-l -one;

4-(4-Ethylthiophen-2-yl)-N-(4-(moφholinomethyl)phenyl)-7H-pyrrolo[2,3-(i]pyrimidin-2- amine;

N-(4-(Moφholinomethyl)phenyl)-4-(4-propylthiophen-2-yl)-7H-pyrrolo[2,3-<i]pyrimidin-2- amine;

N-(3-(4-Methylpiperazin-l-yl)phenyl)-4-(4-(morpholinomethyl)thiophen-2-yl)-7H- pyrrolo[2,3-_<i]pyrimidin-2-amine;

2-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-(i]pyrimidin-4- yl)benzo[b]thiophene-5-carbonitrile;

4-(4-((Diethylamino)methyl)thiophen-2-yl)-N-(4-(4-methylpiperazin-l-yl)phenyl)-7H- pyrrolo[2,3-_<i]pyrimidin-2-amine; 84 [5-(2-{ [4-(lH-Imidazol-l-yl)phenyl]amino}-7H-pyrrolo[2,3-^]pyrimidin-4-yl)-3-

85 methylthiophen-2-yl] methanol;

86 [5-(2-{ [4-(lH-imidazol-l-yl)phenyl]amino}-7H-pyrrolo[2,3-J]pyrimidin-4-yl)-3-

87 methylthiophen-2-yl] methyl acetate;

88 [3-Methyl-5-(2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino}-7H-pyrrolo[2,3-(i]pyrimidin-4-

89 yl)thiophen-2-yl]methanol;

90 {3-Methyl-5-[2-({4-[(2-methyl-lH-imidazol-l-yl)methyl]phenyl]amino}-7H-pyrrolo[2,3-

91 d]pyrimidin-4-yl)thiophen-2-yl}methanol;

92 N-[4-(4-Methylpiperazin-l-yl)phenyl]-4-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)-7H-

93 pyrrolo[2,3-<i]pyrimidin-2-amine;

94 N-[4-(4-Methylpiperazin-l-yl)phenyl]-4-[5-(methylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-

95 c]pyridine-2-yl]-7H-pyrrolo[2,3-(i]pyrimidin-2-amine;

96 4-(5-Acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)- N-[4-(4-methylpiperazin-l-

97 yl)phenyl]-7H-pyrrolo[2,3-(i]pyrimidin-2-amine;

98 4-[5-(2,2-Dimethylpropanoyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl]-N-[4-(4-

99 methylpiperazin-l-yl)phenyl]-7H-pyrrolo[2,3-(i]pyrimidin-2-amine;

100 N,N-Diethyl-2-(2-{ [4-(4-methylpiperazin-l-yl)phenyl]amino}-7H-pyrrolo[2,3-J]pyrimidin-4-

101 yl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide;

102 N-[4-(4-Methylpiperazin-l-yl)phenyl]-4-[5-(pyridin-3-ylcarbonyl)-4,5,6,7-

103 tetrahydrothieno[3,2-c]pyridine-2-yl]-7H-pyrrolo[2,3-(i]pyrimidin-2-amine;

104 N-[3-(4-Methylpiperazin-l-yl)phenyl]-4-[5-(methylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-

105 c]pyridine-2-yl]-7H-pyrrolo[2,3-(i]pyrimidin-2-amine;

106 4-(5-Acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)- N-[3-(4-methylpiperazin-l-

107 yl)phenyl]-7H-pyrrolo[2,3-_<i]pyrimidin-2-amine;

108 4-[5-(2,2-Dimethylpropanoyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)- N-[3-(4-

109 methylpiperazin-l-yl)phenyl]-7H-pyrrolo[2,3-(i]pyrimidin-2-amine; 110 N,N-Diethy\-2-(2-{ [3-(4-methylpiperazin-l-yl)phenyl]amino}-7H-pyrrolo[2,3-^]pyrimidin-4-

111 yl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide;

112 N-[3-(4-Methylpiperazin-l-yl)phenyl]-4-[5-(pyridin-3-ylcarbonyl)-4,5,6,7-

113 tetrahydrothieno[3,2-c]pyridine-2-yl]-7H-pyrrolo[2,3-^]pyrimidin-2-amine;

114 4-[5-(Cyclopropylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl]-N-[3-(4-

115 methylpiperazin-l-yl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-2-amine;

116 N-[3-(4-Methylpiperazin-l-yl)phenyl]-4-[5-(morpholin-4-ylcarbonyl)-4,5,6,7-

117 tetrahydrothieno[3,2-c]pyridine-2-yl]-7H-pyrrolo[2,3-(i]pyrimidin-2-amine;

118 Λ/,N-Dimethyl-2-(2-{ [3-(4-methylpiperazin-l-yl)phenyl]amino}-7H-pyrrolo[2,3-(i]pyrimidin-

119 4-yl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-sulfonamide;

120 4-{5-[(Dimethylamino)acetyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl}-N-[3-(4-

121 methylpiperazin-l-yl)phenyl]-7H-pyrrolo[2,3-(i]pyrimidin-2-amine;

122 N-[3-(4-Methylpiperazin-l-yl)phenyl]-4-[5-(trifluoroacetyl)-4,5,6,7-tetrahydrothieno[3,2-

123 c]pyridin-2-yl]-7H-pyrrolo[2,3-(i]pyrimidin-2-amine;

124 4-(5-Acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-N-[4-(2-pyrrolidin-l-

125 ylethoxy)phenyl]-7H-pyrrolo[2,3-^]pyrimidin-2-amine;

126 4-[5-(Methylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl]-N-[4-(2-pyrrolidin-l-

127 ylethoxy)phenyl]-7H-pyrrolo[2,3-^]pyrimidin-2-amine;

128 N,N-Diethy\-2-(2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl] -amino }-7H-pyrrolo [2,3- J]pyrimidin-4-

129 yl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide;

130 N,N-Bis-(l-methylethyl)-2-(2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl]-amino}-7H-pyrrolo[2,3-

131 J]pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide;

132 4-[5-(Pyridin-3-ylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl]-N-[4-(2-pyrrolidin-l-

133 ylethoxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-2-amine;

134 N-fer?-Butyl-2-(2-{[4-(2-pyrrolidin-l-ylethoxy)phenyl]amino}-7H-pyrrolo[2,3-(i]pyrimidin-4-

135 yl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide; 136 4-{5-[(5-Methylisoxazol-3-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl}-N-[4-(2-

137 pyrrolidin-l-ylethoxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-2-amine;

138 4-[5-(4,6-Dimethoxy-l,3,5-triazin-2-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl]-N-[4-(2-

139 pyrrolidin-l-ylethoxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-2-amine;

140 [3-(4-Methyl-piperazin-l-ylmethyl)-phenyl]-[4-(4-methyl-thiophen-2-yl)-7H-pyrrolo[2,3-

141 d]pyrimidin-2-yl] -amine;

142 [4-(4-Methyl-thiophen-2-yl)-7H-pyrrolo[2,3-<i]pyrimidin-2-yl]-(3-piperazin-l-yl-phenyl)-

143 amine;

144 4-Imidazol-l-ylmethyl-phenyl)-[4-(4-methyl-thiophen-2-yl)-7H-pyrrolo[2,3-(i]pyrimidin-2-

145 yl] -amine;

146 [4-(4-Methyl-piperazin-l-yl)-phenyl]-[4-(4-phenyl-thiophen-2-yl)-7H-pyrrolo[2,3-

147 d]pyrimidin-2-yl] -amine;

148 {4-[4-(3-Isopropyl-phenyl)-thiophen-2-yl]-7H-pyrrolo[2,3-J]pyrimidin-2-yl}-[4-(4-methyl-

149 piperazin-l-yl)-phenyl] -amine;

150 [3-(4-Methyl-piperazin-l-yl)-phenyl]-[4-(4-methyl-thiophen-2-yl)-7Η-pyrrolo[2,3-

151 d]pyrimidin-2-yl] -amine;

152 {4-[5-(3,5-Dimethyl-isoxazol-4-yl)-thiophen-2-yl]-7H-pyrrolo[2,3-J]pyrimidin-2-yl}-[3-(4-

153 methyl-piperazin- l-yl)-phenyl] -amine;

154 (4-Benzo[b]thiophen-2-yl-7H-pyrrolo[2,3-(i]pyrimidin-2-yl)-[3-(4-methyl-piperazin-l-yl)-

155 phenyl] -amine;

156 [4-(5-Methyl-benzo[b]thiophen-2-yl)-7Η-pyrrolo[2,3-d]pyrimidin-2-yl]-[3-(4-methyl-

157 piperazin-l-yl)-phenyl] -amine;

158 2-{2-[4-(2-Methyl-imidazol-l-ylmethyl)-phenylamino]-7H-pyrrolo[2,3-J]pyrimidin-4-yl}-6,7-

159 dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid diethylamide;

160 [4-(4-Ethynyl-thiophen-2-yl)-7H-pyrrolo[2,3-J]pyrimidin-2-yl]-[4-(2-methyl-imidazol-l-

161 ylmethyl) -phenyl] - amine ; 162 (2- { 2- [4-(2-Methyl-imidazol- 1 -ylmethyl)-phenylamino] -7H-pyrrolo [2,3- J]pyrimidin-4-yl } -

163 6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-pyridin-3-yl-methanone;

164 N-(4-((2-methyl-lΗ-imidazol-l-yl)methyl)phenyl)-4-(5-(methylsulfonyl)-4,5,6,7-

165 tetrahydrothieno[3,2-c]pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine;

166 2-{2-[4-(2-Methyl-imidazol-l-ylmethyl)-phenylamino]-7H-pyrrolo[2,3-J]pyrimidin-4-yl}-6,7-

167 dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid ethylamide;

168 2-{2-[4-(2-Methyl-imidazol-l-ylmethyl)-phenylamino]-7H-pyrrolo[2,3-J]pyrimidin-4-yl}-6,7-

169 dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid te/t-butylamide;

170 [3-(4-Methyl-piperazine-l-sulfonyl)-phenyl]-[4-(4-methyl-thiophen-2-yl)-7H-pyrrolo[2,3-

171 d]pyrimidin-2-yl] -amine;

172 (5-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-(i]pyrimidin-4-yl)-3-

173 methylthiophen-2-yl)methanol;

174 3-Methyl-5-{2-[4-(methyl-piperazin-l-yl)phenylamino]-7Η-pyrrolo[2,3-d]pyrimidin-4-yl}-

175 thiophene-2-carbaldehyde oxime;

176 (5-(2-(4-(Morpholinomethyl)phenylamino)-7H-pyrrolo[2,3-J]pyrimidin-4-yl)-3

177 methylthiophen-2-yl)methanol;

178 (5-(2-(3-(Morpholinomethyl)phenylamino)-7H-pyrrolo[2,3-J]pyrimidin-4-yl) 3-

179 methylthiophen-2-yl)methanol;

180 l-(5-(2-(3-(Morpholinomethyl)phenylamino)-7H-pyrrolo[2,3-J]pyrimidin-4-yl)-3-

181 methylthiophen-2-yl)propan- 1 -ol;

182 2-(2-(4-(4-Methylpiperazin-l-yl)phenylamino)-7Η-pyrrolo[2,3-d]pyrimidin-4-

183 yl)benzo[b]thiophene-6-carbonitrile;

184 2-(2-(3-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-J]pyrimidin-4-

185 yl)benzo[b]thiophene-6-carbonitrile;

186 2-(2-(3-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-(i]pyrimidin-4-

187 yl)benzo[b]thiophene-5-carbonitrile; 188 l-(2-(2-(3-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-^]pyrimidin-4-

189 yl)benzo[b]thiophen-5-yl)pentan-l-one;

190 4-(6-(lH-Tetrazol-5-yl)benzo[b]thiophen-2-yl)-N-(4-(2-(pyrrolidin-l-yl)ethoxy)phenyl)-7H-

191 pyrrolo[2,3-_<i]pyrimidin-2-amine;

192 2-(2-(4-(2-(Pyrrolidin-l-yl)ethoxy)phenylamino)-7H-pyrrolo[2,3-J]pyrimidin-4-

193 yl)benzo[b]thiophene-5-carbonitrile;

194 l-(2-(2-(4-(2-(Pyrrolidin-l-yl)ethoxy)phenylamino)-7H-pyrrolo[2,3-J]pyrimidin-4-

195 yl)benzo[b]thiophen-5-yl)pentan-l-one;

196 5-(2-(3-(4-Methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-(i]pyrimidin-4-yl)-3-

197 methylthiophene-2-carbonitrile;

198 4-(4-Methylthiophen-2-yl)-N-(4-morpholin-4-ylphenyl)-7H-pyrrolo[2,3-(i]pyrimidin-2-amine;

199 N-(4-(2-(Dimethylamino)ethoxy)phenyl)-4-(4-methylthiophen-2-yl)-7H-pyrrolo[2,3-

200 d] pyrimidin-2- amine;

201 4-(4-Methylthiophen-2-yl)-N-[4-(l,3-oxazol-5-yl)phenyl]-7H-pyrrolo[2,3-J]pyrimidin-2-

202 amine;

203 N-{4-[2-(lH-Benzimidazol-2-yl)ethyl]phenyl}-4-(4-methylthiophen-2-yl)-7H-pyrrolo[2,3-

204 d] pyrimidin-2- amine;

205 4-(4-Methylthiophen-2-yl)-N-[4-(2-moφholin-4-ylethoxy)phenyl]-7H-pyrrolo[2,3-

206 d] pyrimidin-2- amine;

207 N-{4-[2-(4-Methylpiperazin-l-yl)ethoxy]phenyl}-4-(4-methylthiophen-2-yl)-7H-pyrrolo[2,3-

208 d] pyrimidin-2- amine;

209 N-{4-[(l-Methylpiperidin-4-yl)oxy]phenyl}-4-(4-methylthiophen-2-yl)-7H-pyrrolo[2,3-

210 d] pyrimidin-2- amine;

211 [4-(4-Methyl-thiophen-2-yl)-7H-pyrrolo[2,3-J]pyrimidin-2-yl]-[3-(2-pyrrolidin-l-yl-ethoxy)-

212 phenyl] -amine;

213 [4-(4-Methyl-thiophen-2-yl)-7Η-pyrrolo[2,3-d]pyrimidin-2-yl]-[4-(2-pyrrolidin-l-yl-ethoxy)-

214 phenyl] -amine; 215 [4-(5-Methyl-thiophen-2-yl)-7H-pyrrolo[2,3-^]pyrimidin-2-yl]-[4-(2-pyrrolidin-l-yl-ethoxy)-

216 phenyl] -amine;

217 3-(2-(2-(4-((2-methyl- lΗ-imidazol- l-yl)methyl)phenylamino)-7Η-pyrrolo[2,3-d]pyrimidin-4-

218 yl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-3-oxopropanenitrile;

219 (E)-3-methyl-5-(2-(4-(2-(pyrrolidin-l-yl)ethoxy)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-

220 yl)thiophene-2-carbaldehyde oxime;

221 4-(4-methyl-5-(lH-tetrazol-5-yl)thiophen-2-yl)-N-(4-(2-(pyrrolidin-l-yl)ethoxy)phenyl)-7H-

222 pyrrolo[2,3-d]pyrimidin-2-amine;

223 N-(4-(azepan- 1 -ylmethyl)phenyl)-4-(4-methylthiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-

224 amine;

225 N-(3-(4-methylpiperazin-l-yl)phenyl)-4-(5-(moφholinosulfonyl)-4,5,6,7-tetrahydrothieno[3,2-

226 c]pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine;

227 (3,5-dimethylisoxazol-4-yl)(2-(2-(3-(4-methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-

228 d]pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methanone;

229 (2,5-dimethyloxazol-4-yl)(2-(2-(3-(4-methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-

230 d]pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methanone;

231 (5-methylisoxazol-3-yl)(2-(2-(3-(4-methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-

232 d]pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methanone;

233 (l-methyl-lH-pyrazol-4-yl)(2-(2-(3-(4-methylpiperazin-l-yl)phenylamino)-7H-pyrrolo[2,3-

234 d]pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methanone; and

235 (l,3-dimethyl-lH-pyrazol-4-yl)(2-(2-(3-(4-methylpiperazin-l-yl)phenylamino)-7H-

236 pyrrolo[2,3-d]pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methanone;

237 or pharmaceutically acceptable salts and/or N-oxides thereof.

29. The compound of any one of claims 1-28 wherein said compound inhibits signaling through any of a JAK pathway.

30. The compound of any one of claims 1-29, wherein said compound inhibits one or more of: JAKl, JAK2, JAK3, and TYK2.

31. The compound of any one of claims 1-30, wherein said compound does not substantially modulate KDR.

32. A method for treating a myeloproliferative disorder in a patient in need thereof, comprising administering an effective amount of a compound of any one of claims 1-28.

33. The method of claim 32, wherein the myeloproliferative disorder is one of: polycythemia vera, myelofibrosis, and essential thrombocythemia.

34. A method for treating polycythemia vera in a patient in need thereof, comprising administering an effective amount of a compound of any one of claims 1-31.

35. A method for treating myelofibrosis in a patient in need thereof, comprising administering an effective amount of a compound of any one of claims 1-31.

36. A method for treating essential thrombocythemia in a patient in need thereof, comprising administering an effective amount of a compound of any one of claims 1-31.

37. A method for treating acute myeloid leukemia (AML) in a patient in need thereof, comprising administering an effective amount of a compound of any one of claims 1-28.

38. A method of treating cancer in a patient in need thereof, comprising administering an effective amount of a compound of any one of claims 1-28.

39. A method of treating an immune disorder and/or inflammation in a patient in need thererof, comprising administering an effective amount of a compound of any one of claims 1- 28.

40. A method of treating respiratory inflammation in a patient in need thererof, comprising administering an effective amount of a compound of any one of claims 1-28.

41. A method of treating asthma in a patient in need thereof, comprising administering an effective amount of a compound of any one of claims 1-28.

42. A method of treating chronic obstructive pulmonary disease (COPD) in a patient in need thereof, comprising administering an effective amount of a compound of any one of claims 1- 28.

43. A method of rheumatoid arthritis (RA) in a patient in need thereof, comprising administering an effective amount of a compound of any one of claims 1-28.

44. A method for treating rheumatoid arthritis (RA), psoriatic arthritis, asthma, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, type I diabetes mellitus, myasthenia gravis, thyroiditis, myocarditis, psoriasis, immunoglobulin nephropathies, uveitis, iritis, scleritis, conjunctivitis, graft versus host disease, multiple myeloma, prostrate cancer, or dermatitis, comprising administering an effective amount of a compound of any one of claims 1-28.

45. A method of treating age related macular degeneration, diabetic macular edema, and/or proliferative diabetic retinopathy, comprising administering an effective amount of a compound of any one of claims 1-28.

46. A composition comprising a compound of any one of claims 1-28 and a pharmaceutically acceptable excipient.

47. The compound of any one of claims 1-28 or Formula I, wherein the compound inhibits JAK2 or TYK2 with an IC₅₀ at least about ten times lower as compared to a compound represented by Formula A:

wherein R₁ and R₂ are as defined in claim 1.

48. A process for forming a compound of Formula I:

wherein

R₁ is a heteroaryl containing at least one S atom, and optionally substituted on a ring carbon by one, two, or three substituents each independently selected from the group consisting of: halo, hydroxyl, nitro, formyl, formamido, cyano, sulfonyl, carboxy, amino, amido, acylamino, carbamoyl, sulphamoyl, alkyl, alkenyl, CF₃, ureido, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, carbaldehyde oxime, N-alkylsulphamoyl, N- alkylcarbamoyl, -OR₁₃R₁₁ or -R₁₃R₁₁;

R₂ is phenyl or pyridinyl, wherein R₂ is optionally substituted on a ring carbon by one, two, or three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, nitro, formyl, formamido, carboxy, sulfonyl, amino, amido, -N-alkyl-amino, carbamoyl, sulphamoyl, CF₃, ureido, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, N-alkylcarbamoyl, -OR₁₁, -OR₁₂R₁₁, or -R₁₂R₁₁;

Rn is independently selected from the group consisting of: aryl, heteroaryl, cycloalkyl and heterocycloalkyl, wherein R₁₁ can be optionally substituted by one to four substituents each independently selected from the group consisting of: halo, alkyl, carbonyl, hydroxyl, alkyl-hydroxyl, nitro, formyl, formamido, carboxy, amino, amido, CF₃, ureido, carbamoyl, sulphamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, N-alkylcarbamoyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl;

R₁₂ is alkylene, -SO₂-, -C(O)-, -SO₂N-alkylene-, or a bond;

R₁₃ is alkylene, alkenylene, -C(O)-, -SO₂-, or a bond; or pharmaceutically acceptable salts and N-oxides thereof,

comprising reacting a compound of Formula IV:

IV

wherein Y is a boronic acid or halogen, with R₂-NH₂ to obtain the compound of Formula I.

49. The process of claim 48, wherein R₂ is

X is N or CR₆;

R₆ is H or alkyl; and

R₇ and R₈, independently for each occurrence, are chosen from the group consisting of: H, heterocycle, -O-heterocycle, -alkylene-heterocycle, -O-alkylene-heterocycle, -SO₂N- alkylene-heterocycle, and -SO₂-heterocycle, wherein said heterocycle is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, alkyl, carbonyl, hydroxyl, nitro, formyl, formamido, carboxy, amino, amido, acylamino, carbamoyl, sulphamoyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N- alkylsulphamoyl, and N-alkylcarbamoyl.