EA046985B1 - 2-(2,4,5-Substituted ANILINO)PYRIMIDINE DERIVATIVES AS EGFR MODULATORS USEFUL FOR TREATMENT OF CANCER - Google Patents

Description

The present invention relates to certain 2-(2,4,5-substituted anilino)pyrimidine compounds and pharmaceutically acceptable salts thereof that may be useful in the treatment or prevention of a disease or medical condition mediated by certain mutated forms of epidermal growth factor receptor (eg, L858R activating mutant, activating mutant with deletion in exon 19 and T790M resistant mutant). Such compounds and their salts may be useful in the treatment or prevention of a number of different malignancies. The invention also relates to pharmaceutical compositions containing these compounds and their salts, particularly useful polymorphic forms of these compounds and salts, intermediate compounds useful in the preparation of these compounds, and methods of treating diseases mediated by a variety of different forms of EGFR using these compounds and their salts

EGFR is a transmembrane protein tyrosine kinase that is a member of the erbB receptor family. Upon binding of a growth factor ligand such as epidermal growth factor (EGF), the receptor may homodimerize with another EGFR molecule or heterodimerize with another family member such as erbB2 (HER2), erbB3 (HER3), or erbB4 (HER4).

Homo- and/or heterodimerization of erbB receptors results in phosphorylation of key tyrosine residues in the intracellular domain and leads to the stimulation of a huge number of intracellular signal transduction pathways involved in cell proliferation and survival. Dysregulation of erbB family signaling triggers tumor cell proliferation, invasion, metastasis, angiogenesis, and survival and has been described in many human malignancies, including lung, head and neck, and breast.

Thus, the ErbB family represents a rational target for anticancer drug development, and a number of agents targeting EGFR or erbB2 are currently available in clinical practice, including gefitinib (IRESSA™), erlotinib (TARCEVA™) and lapatinib (TYKERB™, TYVERB ™). A detailed description of erbB receptor signaling and its involvement in tumorigenesis is presented in the New England Journal of Medicine (2008), Vol. 358, 1160-74 and Biochemical and Biophysical Research Communications (2004), Vol. 319, 1-11.

It was reported in 2004 (Science [2004], Vol. 304, 1497-500, and New England Journal of Medicine [2004], Vol. 350, 2129-39) that activating mutations in EGFR correlated with response to gefitinib therapy in non-small cell disease. lung cancer (NSCLC). The most common EGFR activating mutations L858R and delE746_A750 result in increased affinity for small molecule tyrosine kinase inhibitors such as gefitinib and erlotinib and decreased affinity for adenosine triphosphate (ATP) compared with wild-type (WT) EGFR. Eventually, acquired resistance to gefitinib or erlotinib therapy occurs, for example through the T790M residue gatekeeper gene mutation, which is reported to be found in 50% of clinically resistant patients. It is believed that this mutation does not sterically interfere with the binding of gefitinib or erlotinib to EGFR, but simply changes the affinity for ATP to levels comparable to WT EGFR.

In light of the importance of this mutation in resistance to existing EGFR-targeted therapies, the authors believe that agents that can inhibit EGFR-carrying gatekeeper gene mutations may be particularly useful in the treatment of cancer.

There remains a need for compounds that can exhibit favorable efficacy profiles against WT EGFR compared to activating mutant forms of EGFR (e.g., L858R EGFR mutant, or delE746_A750 mutant, or EGFR exon 19 deletion mutant), and/or resistant mutant forms of EGFR ( for example, the T790M EGFR mutant), and/or selectively for other enzyme receptors, which may make the compounds particularly promising for development as therapeutic agents. In this regard, there remains a need for compounds that show a higher degree of inhibition of certain activating or resistant mutant forms of EGFR, while at the same time showing relatively low inhibition of WT EGFR. Such compounds are expected to be more suitable as therapeutic agents, particularly for the treatment of cancer, due to the reduction in toxicological features associated with WT EGFR inhibition. Such toxicological signs are known to manifest as such in humans in the form of skin rashes and/or diarrhea. Applicants have unexpectedly discovered that one or more 2-(2,4,5-substituted anilino)pyrimidine compounds have high potency against several mutant forms of EGFR, while exhibiting relatively low inhibition of WT EGFR.

The compound(s) of the invention may also exhibit favorable physical properties (eg, high aqueous solubility, high permeability, and/or low plasma protein binding), and/or favorable toxicity profiles (eg, reduced hERG blocking capacity), and/or favorable metabolic profiles compared to other known EGFR/EGFR mutant inhibitors. Thus, such compound(s) may be particularly useful in the treatment of disease states in which EGFR and/or activating mutations are involved

- 1 046985

EGFR and/or resistant EGFR mutations, for example in cancer treatment.

In the first aspect of the invention there is provided a compound of formula (I)

(O, where G is selected from 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, Sh-indol-3-yl, 1-methyl-Shindol-3-yl and pyrazolo[1 ,5-a]pyridin-3-yl;

R ¹ is selected from hydrogen, fluorine, chlorine, methyl and cyano;

R ² is selected from methoxy and methyl;

R ³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl, (3S)-3-(dimethylamino)pyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl, [2-(dimethylamino )ethyl](methyl)amino, [2-(methylamino)ethyl](methyl)amino, 5-methyl-2,5-diazaspiro[3.4]oct-2-yl, (3aR,6aR)-5-methylhexa-hydropyrrolo [3,4-b]pyrrol-1(2H)yl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl, 4-[2-(dimethylamino)- 2-oxoethyl]piperazin-1 -yl, methyl[2-(4-methylpiperazin-1 -yl)ethyl]amino, methyl[2-(morpholin-4-yl)ethyl]amino, 1-amino-1,2, 3,6-tetrahydropyridin-4-yl and 4-[(2S)-2-aminopropanoyl]piperazin-1-yl;

or a pharmaceutically acceptable salt thereof.

In one embodiment, a compound of formula (I) is provided as shown above, wherein

G selected from 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, III-indol-3-yl, 1-methyl-III-indol-3-yl and pyrazolo[1,5-a ]pyridin-3-yl;

R ¹ is selected from hydrogen, fluorine, chlorine, methyl and cyano;

R ² is selected from methoxy and methyl; and

R ³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl, (3S)-3-(dimethylamino)pyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl, [2-(dimethylamino )ethyl](methyl)amino, 5-methyl-2,5-diazaspiro[3.4]oct2-yl, (3aR,6aR)-5-methylhexa-hydropyrrolo[3,4-b]pyrrol-1(2H)-yl , 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl, 4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl, methyl[2- (4methylpiperazin-1-yl)ethyl]amino, methyl[2-(morpholin-4-yl)ethyl]amino, 1-amino-1,2,3,6-tetrahydropyridin-4-yl and 4-[(2S) -2-aminopropanoyl]piperazin-1-yl;

or a pharmaceutically acceptable salt thereof.

In one embodiment, a compound of formula (I) is provided as shown above, wherein

G is selected from N-indol-3-yl, 1-methyl-N-indol-3-yl and pyrazolo[1,5-a]pyridin-3-yl;

R ¹ is selected from hydrogen, fluorine, chlorine, methyl and cyano;

R ² is selected from methoxy and methyl;

R ³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl, (3S)-3-(dimethylamino)pyrrolidin-1-yl, 3(dimethylamino)azetidin-1-yl, [2-(dimethylamino) ethyl](methyl)amino, 5-methyl-2,5-diazaspiro[3.4]oct-2yl, (3aR,6aR)-5-methylhexa-hydropyrrolo[3,4-b]pyrrol-1(2H)-yl, 1-methyl-1,2,3,6-tetrahydropyridin4-yl, 4-methylpiperizin-1-yl, 4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl, methyl[2-(4- methylpiperazin-1-yl)ethyl]amino, methyl[2-(morpholin-4-yl)ethyl]amino, 1-amino-1,2,3,6-tetrahydropyridin-4yl and 4-[(2S)-2- aminopropanoyl]piperazin-1-yl;

or a pharmaceutically acceptable salt thereof.

A suitable pharmaceutically acceptable salt of the compound of formula (I) is, for example, an acid addition salt. For example, an acid addition salt can be formed using an inorganic or organic acid. An acid addition salt can be formed using an inorganic acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. The acid addition salt can be formed using an organic acid selected from trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid acid, benzenesulfonic acid and para-toluenesulfonic acid.

In one embodiment, the mesylate salt of N(2-{2-dimethylamino-ethyl-methylamino}-4methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)-prop- 2-enamide.

It should be understood that the compound of formula (I) and its pharmaceutically acceptable salts may exist in solvated forms and non-solvated forms, for example, the solvated form may be a hydrated form. It should be understood that the present invention covers all such solvated and non-solvated forms.

A compound of formula (I) may be administered in the form of a prodrug, which degrades in the human or animal body to produce a compound of formula (I). Examples of prodrugs include

- 2 046985 in vivo hydrolyzable esters of the compound of formula (I). In vivo hydrolyzable esters can be formed by esterification of the hydroxyl group in the compound of formula (I). Various forms of prodrugs are known in the art. For example, such prodrug derivatives can be found in:

a) Design of Products, edited by H. Bundgaard, (Elsevier, 1985), and Methods in

Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985);

b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.

Bundgaard, Chapter 5 “Design and Application of Prodrugs”, by H. Bundgaard p. 113-191 (1991);

c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and N.

Kakeya, et al., Chern Pharm Bull, 32, 692 (1984).

In one aspect of the invention there are provided compounds of formula (I) that inhibit one or more activating or resistance mutations of EGFR, for example the L858R activating mutant, the activating EGFR exon 19 deletion mutant and the T790M resistance mutant. Advantageously, such compounds may be useful for treating cancer in a patient who has developed or is at risk of developing a level of resistance to that of existing EGFR inhibitor-based therapies.

In one aspect, compounds of formula (I) are provided that exhibit a higher degree of inhibition of activating or resistant mutant forms of EGFR compared to WT EGFR. Such compounds are expected to be more suitable as therapeutic agents, particularly for the treatment of cancer, due to the reduction in toxicological features associated with WT EGFR inhibition. Such toxicological signs are known to manifest as such in humans in the form of skin rashes and/or diarrhea.

In one embodiment, a compound of formula (I) is provided as shown above, wherein

G is selected from W-indol-3-yl;

R ¹ is selected from hydrogen, chlorine, methyl and cyano;

R ² represents methoxy;

R ³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl, (3S)-3-(dimethylamino)pyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl, [2-(dimethylamino )ethyl](methyl)amino, 5-methyl-2,5-diazaspiro[3.4]oct2-yl, (3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl, 1 -methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl, 4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl, methyl[2-(4methylpiperazine -1-yl)ethyl]amino, methyl[2-(morpholin-4-yl)ethyl]amino, 1-amino-1,2,3,6-tetrahydropyridin-4-yl and 4-[(2S)-2 -amino-propanoyl]piperazin-1-yl;

or a pharmaceutically acceptable salt thereof.

In a further embodiment there is provided a compound of formula (I) as shown above, wherein

G is selected from W-indol-3-yl;

R ¹ is selected from hydrogen, chlorine, methyl and cyano;

R ² represents methoxy;

R ³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl, [2-(dimethylamino)ethyl](methyl)amino, 1-methyl-1,2 ,3,6-tetrahydropyridin-4-yl and 4-methylpiperizin-1yl;

or a pharmaceutically acceptable salt thereof.

In a further embodiment there is provided a compound of formula (I) as shown above, wherein

G represents 1-methyl-III-indol-3-yl;

R ¹ is selected from hydrogen, chlorine, methyl and cyano;

R ² represents methoxy;

R ³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl, (3S)-3-(dimethylamino)pyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl, [2-(dimethylamino )ethyl](methyl)amino, 5-methyl-2,5-diazaspiro[3.4]oct2-yl, (3aR,6aR)-5-methyl-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl , 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl, 4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl, methyl[2- (4methylpiperazin-1-yl)ethyl]amino, methyl[2-(morpholin-4-yl)ethyl]amino, 1-amino-1,2,3,6-tetrahydropyridin-4-yl and 4-[(2S) -2-aminopropanoyl]piperazin-1-yl;

or a pharmaceutically acceptable salt thereof.

In a further embodiment there is provided a compound of formula (I) as shown above, wherein

G represents 1-methyl-III-indol-3-yl;

R ¹ is selected from hydrogen, chlorine, methyl and cyano;

R ² represents methoxy;

R ³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl,

[2-(dimethylamino)ethyl](methyl)amino and 4-methylpiperizin-1-yl;

- 3 046985 or a pharmaceutically acceptable salt thereof.

In a further embodiment there is provided a compound of formula (I) as shown above, wherein

G is pyrazolo[1,5-a]pyridin-3-yl;

R ¹ is selected from hydrogen, chlorine, methyl and cyano;

R ² represents methoxy;

R ³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl, (3S)-3-(dimethylamino)pyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl, [2-(dimethylamino )ethyl](methyl)amino, 5-methyl-2,5-diazaspiro[3.4]oct2-yl, (3aR,6aR)-5-methylhexa-hydropyrrolo[3 D-EDpyrrol-YUSH-yl, 1 -methyl-1 ,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl, 4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl, methyl[2-(4methylpiperazin-1-yl )ethyl]amino, methyl[2-(morpholin-4-yl)ethyl]amino, 1-amino-1,2,3,6-tetrahydropyridin-4-yl and 4-[(2S)-2-aminopropanoyl]piperazine -1-silt;

or a pharmaceutically acceptable salt thereof.

In a further embodiment there is provided a compound of formula (I) as shown above, wherein

G is pyrazolo[1,5-a]pyridin-3-yl;

R ¹ is selected from hydrogen, chlorine, methyl and cyano;

R ² represents methoxy;

R ³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl, (3S)-3-(dimethylamino)pyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl, [2-(dimethylamino )ethyl](methyl)amino, 5-methyl-2,5-diazaspiro[3.4]oct2-yl, (3aR,6aR)-5-methyl-hexahydropyrrolo[3 D-^pyrrol-1-yl, 1-methyl- 1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl, 4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl, methyl[2-(4methylpiperazin-1 - yl)ethyl]amino, methyl[2-(morpholin-4-yl)ethyl]amino, 1-amino-1,2,3,6-tetrahydropyridin-4-yl and 4-[(2S)-2-aminopropanoyl] piperazin-1-yl;

or a pharmaceutically acceptable salt thereof.

In a further embodiment there is provided a compound of formula (I) as shown above, wherein

G is 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl;

R ¹ is selected from hydrogen, chlorine, methyl and cyano;

R ² represents methoxy;

R ³ is selected from [2-(dimethylamino)ethyl](methyl)amino, (3aR,6aR)-5-methyl-hexahydropyrrolo[3,4EDpyrrol-YUSH-yl, (3R)-3-(dimethylamino)pyrrolidin-1- yl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 3-(dimethylamino)azetidin-1-yl, 5-methyl-2,5-diazaspiro[3.4]oct-2-yl;

or a pharmaceutically acceptable salt thereof.

In a further embodiment there is provided a compound of formula (I) as shown above, wherein

G is 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl;

R ¹ represents hydrogen;

R ² represents methoxy;

R ³ is selected from [2-(dimethylamino)ethyl](methyl)amino, (3aR,6aR)-5-methyl-hexahydropyrrolo[3,4EDpyrrol-YUSH-yl, (3R)-3-(dimethylamino)pyrrolidin-1- yl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 3-(dimethylamino)azetidin-1-yl, 5-methyl-2,5-diazaspiro[3.4]oct-2-yl;

or a pharmaceutically acceptable salt thereof.

In one embodiment, a compound of formula (I) is provided as shown above, wherein

G represents 1H-indol-3-yl or 1-methyl-III-indol-3-yl;

R ¹ represents hydrogen;

R ² represents methoxy;

R ³ is [2-(dimethylamino)ethyl](methyl)amino or [2-(methylamino)ethyl](methyl)amino;

or a pharmaceutically acceptable salt thereof.

Some group variable values are as follows. Such meanings may be used in combination with any of the definitions, formulas, aspects or embodiments defined herein to form further embodiments of the invention:

G represents 1H-indol-3-yl;

G represents 1-methyl-III-indol-3-yl;

G is pyrazolo[1,5-a]pyridin-3-yl;

G is 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl;

R ¹ represents hydrogen;

R ¹ represents chlorine;

R ¹ represents methyl;

R ¹ represents cyano;

R ² represents methoxy;

R ³ is (3R)-3-(dimethylamino)pyrrolidin-1-yl;

R ³ is (3S)-3-(dimethylamino)pyrrolidin-1-yl;

R ³ is 3-(dimethylamino)azetidin-1-yl;

R ³ is [2-(dimethylamino)ethyl](methyl)amino;

- 4 046985

R ³ is [2-(methylamino)ethyl](methyl)amino;

R ³ is 5-methyl-2,5-diazaspiro[3.4]oct-2-yl;

R ³ is (3aK,6aK)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl;

R ³ represents 1-methyl-1,2,3,6-tetrahydropyridin-4-yl;

R ³ is 4-methylpiperizin-1-yl;

R ³ is 4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl;

R ³ represents methyl[2-(4-methylpiperazin-1-yl)ethyl]amino;

R ³ is methyl[2-(morpholin-4-yl)ethyl]amino;

R ³ represents 1-amino-1,2,3,6-tetrahydropyridin-4-yl;

R ³ is 4-[(2S)-2-aminopropanoyl]piperazin-1-yl.

In a further embodiment of the invention relating to any claim or embodiment of a compound of formula (I) described or derived herein, or a pharmaceutically acceptable salt thereof, such claim or embodiment is provided wherein one of the exemplified compounds of this application is not claimed. For the avoidance of doubt, the example compounds are those listed as Example 1, Example 2, and so on, in the experimental section described below.

Thus, for example, in one embodiment there is provided a compound of formula (I) as shown above, wherein

G selected from 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, III-indol-3-yl, 1-methyl-III-indol-3-yl and pyrazolo[1,5-a ]pyridin-3-yl;

R ¹ is selected from hydrogen, fluorine, chlorine, methyl and cyano;

R ² is selected from methoxy and methyl;

R ³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl, (3S)-3-(dimethylamino)pyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl, [2-(dimethylamino )ethyl](methyl)amino, [2-(methylamino)ethyl](methyl)amino, 5-methyl-2,5-diazaspiro[3.4]oct-2-yl, (3αR,6αR)-5-methylhexahydropyrrolo[3 ,4-b]pyrrol-1(2H)yl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl, 4-[2-(dimethylamino)-2oxoethyl] piperazin-1 -yl, methyl[2-(4-methylpiperazin-1 -yl)ethyl]amino, methyl[2-(morpholin-4-yl)ethyl]amino, 1-amino-1,2,3,6- tetrahydropyridin-4-yl and 4-[^)-2-aminopropanoyl]piperazin-1-yl;

or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is not X(2-{2-dimethylaminoethyl-methylamino}-4methoxy-5-{[4-(1-methyl-indol-3-yl)pyrimidin-2- yl]amino}phenyl)-prop-2-enamide.

Thus, in one embodiment there is provided a compound of formula (I) as shown above, wherein

G selected from 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, III-indol-3-yl, 1-methyl-III-indol-3-yl and pyrazolo[1,5-a ]pyridin-3-yl;

R ¹ is selected from hydrogen, fluorine, chlorine, methyl and cyano;

R ² is selected from methoxy and methyl;

R ³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl, (3S)-3-(dimethylamino)pyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl, [2-(dimethylamino )ethyl](methyl)amino, 5-methyl-2,5-diazaspiro[3.4]oct2-yl, (3αR,6αR)-5-methylhexa-hydropyrrolo[3-EDpyrrolLCY-yl, 1-methyl-1,2 ,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl, 4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl, methyl[2-(4methylpiperazin-1 -yl)ethyl ]amino, methyl[2-(morpholin-4-yl)ethyl]amino, 1-amino-1,2,3,6-tetrahydropyridin-4-yl and 4-[(2S)-2-aminopropanoyl]piperazine-1 -ila;

or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is not X(2-{2-dimethylaminoethyl-methylamino}-4methoxy-5-{[4-(1-methyl-indol-3-yl)pyrimidin-2- yl]amino}phenyl)-prop-2-enamide.

Thus, in a further embodiment there is provided a compound of formula (I) as shown above, wherein

G is selected from N-indol-3-yl, 1-methyl-N-indol-3-yl and pyrazolo[1,5-a]pyridin-3-yl;

R ¹ is selected from hydrogen, fluorine, chlorine, methyl and cyano;

R ² is selected from methoxy and methyl;

R ³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl, (3S)-3-(dimethylamino)pyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl, [2-(dimethylamino )ethyl](methyl)amino, 5-methyl-2,5-diazaspiro[3.4]oct2-yl, (3αR,6αR)-5-methylhexa-hydropyrrolo[3-EDpyrrolLCY-yl, 1-methyl-1,2 ,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl, 4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl, methyl[2-(4methylpiperazin-1 -yl)ethyl ]amino, methyl[2-(morpholin-4-yl)ethyl]amino, 1-amino-1,2,3,6-tetrahydropyridin-4-yl and 4-[(2S)-2-aminopropanoyl]piperazine-1 -ila;

or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is not X(2-{2-dimethylaminoethyl-methylamino}-4methoxy-5-{[4-(1-methyl-indol-3-yl)pyrimidin-2- yl]amino}phenyl)-prop-2-enamide.

Additional embodiments of the invention provide any of the example compounds (as referred to herein in the Experimental Section, in their free base form).

Additional embodiments of the invention provide any of the example compounds (as referred to herein in the experimental section, in their free base form) or pharmaceutically

- 5 046985 acceptable salts.

Thus, examples of just some of the above embodiments are given below.

In one embodiment, N-(5-{[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-2-{(3R)3-dimethylaminopyrrolidin-1 -yl}- 4-methoxyphenyl)prop-2-enamide.

In one embodiment, K-(5-{[5-chloro-4-(N-indol-3-yl)pyrimidin-2-yl]amino}-2-{2dimethylaminoethyl-methylamino}-4-methoxyphenyl)prop-2 is provided -enamide or a pharmaceutically acceptable salt thereof.

In one embodiment, K-(5-{[5-chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}-2{2-dimethylaminoethyl-methylamino}-4-methoxyphenyl)-prop is provided -2-enamid.

In one embodiment, K-(5-{[5-cyano-4-(III-indol-3-yl)pyrimidin-2-yl]amino}-4methoxy-2-{4-methylpiperazin-1-yl}phenyl) is provided prop-2-enamide or a pharmaceutically acceptable salt thereof.

In one embodiment, K-(5-{[5-cyano-4-(III-indol-3-yl)pyrimidin-2-yl]amino}-4methoxy-2-{4-methylpiperazin-1-yl}phenyl) is provided prop-2-enamide.

In one embodiment, K-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide or its pharmaceutically acceptable salt.

In one embodiment, K-{2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide is provided.

In one embodiment, K-(5-{[5-cyano-4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}-2{2-dimethylaminoethyl-methylamino}-4-methoxyphenyl)prop- 2-enamide or a pharmaceutically acceptable salt thereof.

In one embodiment, K-(5-{[5-cyano-4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}-2{2-dimethylaminoethyl-methylamino}-4-methoxyphenyl)prop- 2-enamid.

In one embodiment, K-{5-[(5-cyano-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2yl)amino]-2-[2-dimethylaminoethylmethylamino]-4-methoxyphenyl} is provided prop-2-enamide or a pharmaceutically acceptable salt thereof.

In one embodiment, K-{5-[(5-cyano-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2yl)amino]-2-[2-dimethylaminoethylmethylamino]-4-methoxyphenyl} is provided prop-2-enamide.

In one embodiment, K-{5-[(5-cyano-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2yl)amino]-2-[3-dimethylaminoazetidin-1-yl]-4- methoxyphenyl}prop-2-enamide or a pharmaceutically acceptable salt thereof.

In one embodiment, K-{5-[(5-cyano-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2yl)amino]-2-[3-dimethylaminoazetidin-1-yl]-4- methoxyphenyl}prop-2-enamide.

In one embodiment, K-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(4,5,6,7tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin- 2-yl]amino}phenyl)prop-2-enamide.

In one embodiment, K-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(4,5,6,7tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin- 2-yl]amino}phenyl)prop-2-enamide or a pharmaceutically acceptable salt thereof.

In one embodiment, K-{2-[2-dimethylaminoethyl-methylamino]-4-methoxy-5-[(4pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]phenyl}prop-2 is provided -enamid.

In one embodiment, K-{2-[2-dimethylaminoethyl-methylamino]-4-methoxy-5-[(4pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]phenyl}prop-2 is provided -enamide or a pharmaceutically acceptable salt thereof.

In one embodiment, K-(2-[2-dimethylaminoethylmethylamino]-5-{[4-(N-indol-3yl)pyrimidin-2-yl]amino}-4-methoxyphenyl)prop-2-enamide is provided.

In one embodiment, K-(2-[2-dimethylaminoethyl-methylamino]-5-{[4-(N-indol-3yl)pyrimidin-2-yl]amino}-4-methoxyphenyl)prop-2-enamide or its pharmaceutically acceptable salt.

In one embodiment, K-(4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}2-[methyl-(2-methylaminoethyl)amino]phenyl)prop- 2-enamide or a pharmaceutically acceptable salt thereof.

In one embodiment, K-(4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}2-[methyl-(2-methylaminoethyl)amino]phenyl)prop- 2-enamid.

Compounds of formula (I) can be prepared by reacting a compound of formula (II)

(P) or salts thereof (wherein G, R ¹ , R ² and R ³ are as defined herein), with an activated acrylic acid derivative (for example, acryloyl chloride or the corresponding active

- 6 046985 ester), in a solvent such as CH2C12, tetrahydrofuran, N,N-dimethylformamide or N.N-dimethylacetamide.

Thus, the intermediates of formula (II) form a further aspect of the present invention.

Thus, in a further aspect of the invention there is provided a compound of formula (II) (as shown above), wherein

G is selected from 1H-indol-3-yl, 1-methyl-1H-indol-3-yl and pyrazolo[1,5-a]pyridin-3-yl;

R ¹ is selected from hydrogen, chlorine, methyl and cyano;

R ² represents methoxy;

R ³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl, (3S)-3-(dimethylamino)pyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl, [2-(dimethylamino )ethyl](methyl)amino, 5-methyl-2,5-diazaspiro[3.4]oct2-yl, (3aK,6aK)-5-methylhexa-hydropyrrolo[3,4-b]pyrrol-1(2H)-yl , 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl, 4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl, methyl[2- (4methylpiperazin-1 -yl)ethyl]amino, methyl[2-(morpholin-4-yl)ethyl]amino, 1-amino-1,2,3,6-tetrahydropyridin-4-yl and 4-[(2S) -2-(tert-butoxycarbonyl)aminopropanoyl]piperazin-1-yl;

or its salt.

In one embodiment, a compound of formula (II) (as shown above) is provided, wherein

G selected from 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl and pyrazolo[1,5-a ] pyridin-3-yl;

R ¹ is selected from hydrogen, chlorine, methyl and cyano;

R ² represents methoxy;

R ³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl, (3S)-3-(dimethylamino)pyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl, [2-(dimethylamino )ethyl](methyl)amino, 5-methyl-2,5-diazaspiro[3.4]oct2-yl, (3aK,6aK)-5-methylhexa-hydropyrrolo[3,4-b]pyrrol-1(2H)-yl , 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl, 4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl, methyl[2- (4methylpiperazin-1 -yl)ethyl]amino, methyl[2-(morpholin-4-yl)ethyl]amino, 1-amino-1,2,3,6-tetrahydropyridin-4-yl and 4-[(2S) -2-(tert-butoxycarbonyl)aminopropanoyl]piperazin-1-yl;

or its salt.

In a further embodiment there is provided a compound of formula (II) (as shown above), wherein

G selected from 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl and pyrazolo[1,5-a ]pyridin-3-yl;

R ¹ is selected from hydrogen, chlorine, methyl and cyano;

R ² represents methoxy;

R ³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl, (3S)-3-(dimethylamino)pyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl, [2-(dimethylamino )ethyl](methyl)amino, [2-(methylamino)ethyl](methyl)amino, 5-methyl-2,5-diazaspiro[3.4]oct-2-yl, (3aK,6aK)-5-methylhexahydropyrrolo[3 ,4-b]pyrrol-1(2H)yl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl, 4-[2-(dimethylamino)-2- oxoethyl]piperazin-1-yl, methyl [2-(4-methylpiperazin-1-yl)ethyl]amino, methyl[2-(morpholin-4-yl)ethyl]amino, 1-amino-1,2,3, 6-tetrahydropyridin-4-yl and 4-[^)-2-aminopropanoyl]piperazin-1-yl;

or its salt.

Additional embodiments of the invention provide any of the intermediates (as referred to herein in the experimental section, in their free base form).

Additional embodiments of the invention provide any of the intermediates (as referred to herein in the experimental section, in their free base form) or pharmaceutically acceptable salts thereof.

Thus, examples of just some of the above embodiments are given below.

In one embodiment, Intermediate 100 or a salt thereof is provided.

Thus, in this case, N-(2-dimethylaminoethyl)-5-methoxy-N-methyl-U-[4-(1methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine is proposed or its salt.

In one embodiment, N-(2-dimethylaminoethyl)-5-methoxy-N-methyl-U-[4-(1methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine is provided.

In one embodiment, Intermediate 168 or a salt thereof is provided.

Thus, in this case, N-(2-dimethylaminoethyl)-U-[4-(1H-indol-3yl)pyrimidin-2-yl]-5-methoxy-N-methylbenzene-1,2,4-triamine or its salt.

In one embodiment, N-(2-dimethylaminoethyl)-U-[4-(1H-indol-3-yl)pyrimidin-2-yl]5-methoxy-N-methylbenzene-1,2,4-triamine is provided.

The amino compounds of formula (II) can be prepared by reduction of the corresponding nitro compounds. When G is indol-3-yl, then the nitrogen atom of the indole group may be protected by a suitable nitrogen protecting group, for example a phenylsulfonyl protecting group. For examples of protecting groups, including protecting groups suitable for protecting nitrogen atoms (as well as means of formation and possible deprotection), see T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, Second Edition, John Wiley & Sons, New York, 1991.

- 7 046985

These additional intermediates form another aspect of the invention.

Thus, in a further aspect of the invention there is provided a compound of formula (III)

(ΠΙ), where G is selected from III-indol-3-yl, 1-methyl-III-indol-3-yl and 1-(N-protecting group)indol-3-yl and pyrazolo[1,5-a]pyridine -3 -ila;

R ¹ is selected from hydrogen, chlorine, methyl and cyano;

R ² represents methoxy;

R ³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl, (3S)-3-(dimethylamino)pyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl, [2-(dimethylamino )ethyl](methyl)amino, 5-methyl-2,5-diazaspiro[3.4]oct2-yl, (3aR,6aR)-5-methylhexa-hydropyrrolo[3,4-b]pyrrol-1(2H)-yl , 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl, 4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl, methyl[2- (4methylpiperazin-1-yl)ethyl]amino, methyl[2-(morpholin-4-yl)ethyl]amino, 1-amino-1,2,3,6-tetrahydropyridin-4-yl and 4-[(2S) -2-(tert-butoxycarbonyl)aminopropanoyl]piperazin-1-yl;

or its salt.

In one embodiment of this aspect of the invention there is provided a compound of formula (III) as shown above, wherein

G selected from 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, III-indol-3-yl, 1-methyl-III-indol-3-yl and 1-(No protecting group) -indol-3-yl and pyrazolo[1,5-a]pyridin-3-yl;

R ¹ is selected from hydrogen, chlorine, methyl and cyano;

R ² represents methoxy;

R ³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl, (3S)-3-(dimethylamino)pyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl, [2-(dimethylamino )ethyl](methyl)amino, 5-methyl-2,5-diazaspiro[3.4]oct2-yl, (3aR,6aR)-5-methylhexa-hydropyrrolo[3,4-b]pyrrol-1(2H)-yl , 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl, 4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl, methyl[2- (4methylpiperazin-1-yl)ethyl]amino, methyl[2-(morpholin-4-yl)ethyl]amino, 1-amino-1,2,3,6-tetrahydropyridin-4-yl and 4-[(2S) -2-(tert-butoxycarbonyl)aminopropanoyl]piperazin-1-yl;

or its salt.

In a further embodiment of this aspect of the invention there is provided a compound of formula (III) as shown above, wherein

G selected from 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, III-indol-3-yl, 1-methyl-III-indol-3-yl and 1G-protecting group)-indole -3-yl and pyrazolo[1,5-a]pyridin-3-yl;

R ¹ is selected from hydrogen, chlorine, methyl and cyano;

R ² represents methoxy;

R ³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl, (3S)-3-(dimethylamino)pyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl, [2-(dimethylamino )ethyl](methyl)amino, [2-(methylamino)ethyl](methyl)amino, 5-methyl-2,5-diazaspiro[3.4]oct-2-yl, (3aR,6aR)-5-methylhexahydropyrrolo[3 ,4-b]pyrrol-1(2R)yl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl, 4-[2-(dimethylamino)-2oxoethyl] piperazin-1-yl, methyl[2-(4-methylpiperazin-1-yl)ethyl]amino, methyl[2-(morpholin-4-yl)ethyl]amino, 1-amino-1,2,3,6- tetrahydropyridin-4-yl and 4-[(2S)-2-aminopropanoyl]piperazin-1-yl;

or its salt.

One example of an N-protecting group in the 1-(N-protecting group)indol-3-yl radical is a phenylsulfonyl group.

In one embodiment, Intermediate 101 or a salt thereof is provided.

Thus, in this case, N-(2-dimethylaminoethyl)-2-methoxy-N-methyl-M-[4-(1methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-1,4- diamine or its salt.

In one embodiment, N-(2-dimethylaminoethyl)-2-methoxy-N-methyl-M-[4-(1methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-1,4-diamine is provided.

In one embodiment, Intermediate 169 or a salt thereof is provided.

Thus, in this case, N-(2-dimethylaminoethyl)-M-[4-(III-indol-3yl)pyrimidin-2-yl]-2-methoxy-N-methyl-5-nitrobenzene-1,4- diamine or its salt.

In one embodiment, N-(2-dimethylaminoethyl)-M-[4-(N-indol-3-yl)pyrimidin-2-yl]2-methoxy-N-methyl-5-nitrobenzene-1,4-diamine is provided.

In one embodiment, Intermediate 175 or a salt thereof is provided.

Thus, in this case, ^-(2-dimethylaminoethyl)-2-methoxy-Jmethyl-J[4-(1

- 8 046985 methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-1,4-diamine or its salt.

In one embodiment, K ⁴ -(2-dimethylaminoethyl)-2-methoxy-K ⁴ -methyl-K ¹ -[4-(1methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-1,4- diamine

Some compounds of formula (III) have an R ³ group attached to the phenyl ring of formula (III) via the nitrogen atom of the R ³ group. These compounds can be prepared by reacting the appropriate amine with a suitable fluorine compound. Such intermediates form another aspect of the invention.

Thus, in an additional aspect of the invention there _is provided a compound of formula (IV) ( ^G ) 1,5-a]pyridin-3-yl;

R ¹ is selected from hydrogen, chlorine, methyl and cyano;

R ² represents methoxy;

or its salt.

In one embodiment of this aspect of the invention there is provided a compound of formula (IV) as set forth above, wherein

G selected from 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, III-indol-3-yl, 1-methyl-III-indol-3-yl and pyrazolo[1,5-a ]pyridin-3-yl;

R ¹ is selected from hydrogen, chlorine, methyl and cyano;

R ² represents methoxy;

or its salt.

In one embodiment, Intermediate 68 or a salt thereof is provided.

Thus, in this case, K-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3yl)pyrimidin-2-amine or a salt thereof is provided.

In one embodiment, K-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(III-indol-3yl)pyrimidin-2-amine is provided.

In one embodiment, Intermediate 129 or a salt thereof is provided.

Thus, in this case, K-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol3-yl)pyrimidin-2-amine or a salt thereof is provided.

In one embodiment, K-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3yl)pyrimidin-2-amine is provided.

In one embodiment, Intermediate 176 or a salt thereof is provided.

Thus, in this case, K-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol3-yl)-pyrimidin-2-amine or a salt thereof is provided.

In one embodiment, K-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine is provided.

Some compounds of formula (III) have an R ³ group attached to the phenyl ring of formula (III) via the nitrogen atom of the R ³ group. These compounds can be prepared by reacting a suitable organoboron compound (eg a borate ester compound) with a suitable aryl bromide or aryl chloride compound. For example, the organoboron compound may be (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-k ³ . Such intermediates form another aspect of the invention.

Thus, in a further aspect of the invention there is provided a compound of formula (V)

(V) where X represents bromine or chlorine;

G selected from 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, III-indol-3-yl, 1-methyl-III-indol-3-yl and pyrazolo[1,5-a ]pyridin-3-yl;

R ¹ is selected from hydrogen, chlorine, methyl and cyano;

R ² represents methoxy;

- 9 046985 or its salt.

In one embodiment of the compound of formula (V), X is bromine.

In one embodiment of the compound of formula (V), X is chlorine.

In one embodiment, Intermediate 145 is provided.

Thus, N(4-bromo-2-methoxy-5-nitrophenyl)-4-(1-methylindol3-yl)pyrimidin-2-amine or a salt thereof is provided herein.

In one embodiment, N(4-bromo-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3yl)pyrimidin-2-amine is provided.

Preferably, the compounds of the present invention can be prepared by reacting a compound of formula (II) with 3-chloropropanoyl chloride in the presence of a base (eg an alkali metal carbonate, eg potassium carbonate) in a suitable solvent, eg acetone. An intermediate of formula (VI) is thus obtained, which can be isolated as a solid (in the form of its free base or as a salt) or it can remain in solution and treated with a base (eg an alkali metal hydroxide, eg NaOH) to converting a compound of formula (VI) into the corresponding compound of formula (I). Thus, the compounds of formula (VI) and its salts are useful chemical intermediates in the formation of compounds of formula (I). Thus, in a further aspect of the invention there is provided a compound of formula (VI) (VI) or a salt thereof, wherein G, R ¹ , R ² and R ³ are as defined herein.

In one embodiment, there is provided a compound of formula (VI) as shown above, or a salt thereof, wherein

G selected from 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, III-indol-3-yl, 1-methyl-III-indol-3-yl and pyrazolo[1,5-a ]pyridin-3-yl;

R ¹ is selected from hydrogen, fluorine, chlorine, methyl and cyano;

R ² is selected from methoxy and methyl;

R ³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl, (3S)-3-(dimethylamino)pyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl, [2-(dimethylamino )ethyl](methyl)amino, [2-(methylamino)ethyl](methyl)amino, 5-methyl-2,5-diazaspiro[3.4]oct-2-yl, (3aR,6aR)-5-methylhexahydropyrrolo[3 ,4-b]pyrrol-1(2H)yl, 1 -methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1 -yl, 4-[2-(dimethylamino)-2- oxoethyl]piperazin-1-yl, methyl[2-(4-methylpiperazin-1-yl)ethyl]amino, methyl[2-(morpholin-4-yl)ethyl]amino, 1-amino-1,2,3, 6-tetrahydropyridin-4-yl and 4-[^)-2-aminopropanoyl]piperazin-1-yl.

In a further embodiment there is provided a compound of formula (VI) as shown above, or a salt thereof, wherein

G is selected from N-indol-3-yl, 1-methyl-N-indol-3-yl and pyrazolo[1,5-a]pyridin-3-yl;

R ¹ is selected from hydrogen, fluorine, chlorine, methyl and cyano;

R ² is selected from methoxy and methyl;

R ³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl, (3S)-3-(dimethylamino)pyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl, [2-(dimethylamino )ethyl](methyl)amino, 5-methyl-2,5-diazaspiro[3.4]oct2-yl, (3aR,6aR)-5-methylhexahydropyrrolo[3,4P]pyrrol-1 (2^-yl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl, 4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl, methyl[2-( 4methylpiperazin-1-yl)ethyl]amino, methyl[2-(morpholin-4-yl)ethyl]amino, 1-amino-1,2,3,6-tetrahydropyridin-4-yl and 4-[(2S)- 2-aminopropanoyl]piperazin-1-yl.

In a further embodiment, Intermediate 174 or a salt thereof is provided.

Thus, in this case, 3-chloro-N[2-[2-dimethylaminoethyl-(methyl)amino]-4methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino is proposed ]phenyl]propanamide or its salt.

In one embodiment, 3-chloro-N[2-[2-dimethylaminoethyl-(methyl)amino]-4-methoxy-5-[[4(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl is provided ]propanamide.

Other intermediates are useful in the preparation of certain compounds of formula (I). Thus, for example, in one embodiment, Intermediate 170 or a salt thereof is provided. In a further embodiment, Intermediate 171 or a salt thereof is provided. In yet another embodiment, Intermediate 172 or a salt thereof is provided. In one embodiment, Intermediate 144 or a salt thereof is provided.

According to a further aspect of the invention, there is provided a pharmaceutical composition containing

- 10 046985 containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, together with a pharmaceutically acceptable diluent or carrier.

The compositions of the invention may be presented in a form suitable for oral administration (for example, tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical application (for example, as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (eg, as a fine powder or liquid aerosol), for administration by insufflation (eg, as a fine powder), or for parenteral administration (eg , as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing, or as a suppository for rectal dosing).

The compositions of the invention can be prepared by conventional techniques using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral administration may contain, for example, one or more coloring agents, sweeteners, flavoring agents and/or preservatives.

The compound of formula (I) is usually administered to a warm-blooded animal in a single dose in the range of 5-5000 mg/m ² animal body area, i.e. approximately 0.1-100 mg/kg, and this usually provides a therapeutically effective dose. A unit dosage form, such as a tablet or capsule, typically contains, for example, 1-250 mg of active ingredient. The daily dosage will vary as needed depending on the organism being treated, the specific route of administration and the severity of the disease being treated. Accordingly, the doctor who is treating a particular patient can determine the optimal dosage.

As used herein, the term therapy also includes prophylaxis unless specifically stated otherwise. The terms therapeutic and therapeutically should be interpreted accordingly.

The term treatment, as used herein, has the ordinary everyday meaning of treating a disease with the goal of complete or partial relief from some or all of its symptoms or correction or compensation of the pathology underlying it.

The term prevention, as used herein, has its ordinary everyday meaning and includes primary prevention of the development of a disease and secondary prevention in which, once a disease has developed, the patient is temporarily or permanently protected from exacerbation or worsening of the disease or the development of new symptoms associated with that disease.

As a result of its inhibitory activity against the L858R EGFR mutant, the T790M EGFR mutant and the activating exon 19 deletion mutant, the compound of formula (I) and its pharmaceutically acceptable salts are expected to be useful in the treatment of diseases or medical conditions mediated solely or in part by EGFR mutant activity, such as cancer. Cancers that may be treatable using a compound of formula (I) or pharmaceutically acceptable salts thereof include ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer, hepatocellular cancer, stomach cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, bile duct cancer, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML ), multiple myeloma, melanoma and mesothelioma, but are not limited to them.

It is contemplated that in the methods of treating cancer mentioned herein, a compound of formula (I) will be administered to a mammal, more particularly a human. Likewise, in the case of using a compound of formula (I) for the treatment of cancer mentioned herein, it is contemplated that the compound of formula (I) will be administered to a mammal, more particularly a human.

According to another aspect of the invention, there is provided a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for use as a drug.

According to a further aspect of the invention, there is provided a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease mediated through the L858R EGFR mutant and/or the T790M EGFR and/or an activating deletion mutant in exon 19. In one In an embodiment of the invention, said disease mediated through the L858R EGFR mutant and/or the T790M EGFR and/or the activating exon 19 deletion mutant is cancer.

According to a further aspect of the invention, there is provided the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease mediated through the L858R EGFR mutant and/or T790M EGFR and/or an activating deletion mutant in exon 19 In one embodiment of the invention, the disease mediated through the L858R EGFR mutant and/or the T790M EGFR and/or the activating exon 19 deletion mutant is cancer.

According to a further aspect of the invention, there is provided the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicinal product.

- 11 046985 means for the treatment of cancer.

According to a further aspect of the invention there is provided a method of using a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for the treatment of cancer.

According to this aspect of the invention, there is provided a method of producing an anticancer effect in a warm-blooded animal, such as a human, in need of such treatment, comprising administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined herein.

According to a further aspect of the invention, there is provided a method of treating a human suffering from a disease that benefits from inhibition of an L858R EGFR mutant and/or a T790M EGFR mutant and/or an activating exon 19 deletion mutant, comprising the steps of administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (I) as defined above, or a pharmaceutically acceptable salt thereof. In one embodiment of the invention, the disease that benefits from inhibition of the L858R EGFR mutant and/or the T790M EGFR mutant and/or the activating exon 19 deletion mutant is cancer.

In any of the aspects or embodiments mentioned herein, where cancer is referred to in a general sense, said cancer may be selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer gland, leukemia, lymphoma, non-Hodgkin's lymphoma, stomach cancer, lung cancer, hepatocellular cancer, stomach cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, bile duct cancer, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML), multiple myeloma, melanoma and mesothelioma.

In any of the aspects or embodiments of the invention where cancer is mentioned in a general sense, the following embodiments may be applicable.

In one embodiment, the cancer is ovarian cancer.

In one embodiment, the cancer is cervical cancer.

In one embodiment, the cancer is colorectal cancer.

In one embodiment, the cancer is breast cancer.

In one embodiment, the cancer is pancreatic cancer.

In one embodiment, the cancer is a glioma.

In one embodiment, the cancer is a glioblastoma.

In one embodiment, the cancer is melanoma.

In one embodiment, the cancer is prostate cancer.

In one embodiment, the cancer is leukemia.

In one embodiment, the cancer is lymphoma.

In one embodiment, the cancer is non-Hodgkin's lymphoma.

In one embodiment, the cancer is gastric cancer.

In one embodiment, the cancer is lung cancer.

In one embodiment, the cancer is non-small cell lung cancer.

In one embodiment, the cancer is hepatocellular carcinoma.

In one embodiment, the cancer is gastric cancer.

In one embodiment, the cancer is a gastrointestinal stromal tumor (GIST).

In one embodiment, the cancer is thyroid cancer.

In one embodiment, the cancer is bile duct cancer.

In one embodiment, the cancer is endometrial cancer.

In one embodiment, the cancer is kidney cancer.

In one embodiment, the cancer is anaplastic large cell lymphoma.

In one embodiment, the cancer is acute myeloid leukemia (AML).

In one embodiment, the cancer is multiple myeloma.

In one embodiment, the cancer is melanoma.

In one embodiment, the cancer is mesothelioma.

The anticancer treatment described above may be used as a single therapy, or it may include, in addition to the compound of the invention, conventional surgery, or radiotherapy, or chemotherapy, or immunotherapy. Such chemotherapy may be administered in parallel, simultaneously, sequentially or separately with treatment with a compound of the invention and may include one or more agents from the following categories of antineoplastic agents:

(1) antiproliferative/antineoplastic drugs and combinations thereof used in medical oncology, such as alkylating agents (eg, cis-platinum, oxaliplatin, carboplatin, cyclophosphamide, chlormethine, melphalan, chlorambucil, busulfan, temozolamide and nitrosoureas); antimetabolites (eg, gemcitabine and antifolates such as fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); against

- 12 046985 tumor antibiotics (for example, anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (eg, vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine and taxoids such as taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (eg, epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan and camptothecin);

(2) cytostatic agents such as antiestrogens (eg, tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxifene), antiandrogens (eg, bicalutamide, flutamide, nilutamide, and cyproterone acetate), luteinizing hormone releasing hormone (LHRH) antagonists, or agonists LHRH (eg, goserelin, leuprorelin, and buserelin), progestogens (eg, megestrol acetate), aromatase inhibitors (eg, anastrozole, letrozole, vorazole, and exemestane), and 5a-reductase inhibitors such as finasteride;

(3) anti-invasive agents (for example, inhibitors of the c-Src family of kinases such as 4-(6-chloro-2,3methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran -4-yloxyquinazoline [AZD0530 (Saracatinib); >(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1yl]-2-methylpyrimidin-4 -ylamino}thiazol-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661) and bosutinib (SKI-606), and metalloproteinase inhibitors such as marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to heparanase);

(4) inhibitors of growth factor function: for example, such inhibitors include anti-growth factor antibodies and anti-growth factor receptor antibodies (eg, anti-erbB2 antibody trastuzumab [Herceptin™], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab [Erbitux, C225] and any antibodies to growth factors and growth factor receptors disclosed by Stern et al., Critical reviews in oncology/haematology, 2005, Vol. such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example, tyrosine kinase inhibitors of the EGFR family, such as >(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis-(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido->(3-chloro-4- fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin family of growth factors; platelet-derived growth factor family inhibitors such as imatinib and/or nilotinib (AMN107); serine/threonine kinase inhibitors (e.g. Ras/Raf signaling inhibitors, such as farnesyltransferase inhibitors, such as sorafenib (BAY 43-9006), tipifarnib (R115777) and lonafarnib (SCH66336)), MEK- and/or AKT-signaling inhibitors kinases, c-kit inhibitors, abl-kinase inhibitors, PI3-kinase inhibitors, Plt3-kinase inhibitors, CSF-1R-kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (eg, AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin-dependent kinase inhibitors, such as CDK2 and/or CDK4 inhibitors;

(5) antiangiogenic agents, such as agents that inhibit the effects of vascular endothelial growth factor [eg, anti-vascular endothelial growth factor antibody bevacizumab [Avastin™] and, for example, VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), vatalanib ( PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1- ylpropoxy)quinazoline (AZD2171;

example 240 in WO 00/47212), compounds such as those disclosed in international application publications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354), and compounds with other mechanisms of action (eg , linomide, inhibitors of ave3 integrin function and angiostatin);

(6) vascular damaging agents such as Combretastatin A4 and the compounds disclosed in International Application Publications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(7) an endothelin receptor antagonist, such as zibotentan (ZD4054) or atrasentan;

(8) antisense therapies, for example, those directed to the targets listed above, such as ISIS 2503, antisense anti-ras;

(9) gene therapy approaches, including, for example, approaches to replace aberrant genes, such as aberrant p53, or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme-prodrug therapy) approaches, such as approaches using cytosine deaminase, thymidine kinase, or bacterial the enzyme nitroreductase, and approaches to increase a patient's tolerance to chemotherapy or radiotherapy, such as multidrug resistance gene therapy; and (10) immunotherapeutic approaches, including, for example, ex vivo and in vivo approaches to increase the immunogenicity of the patient's tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony-stimulating factor, approaches to reduce T cell anergy , approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines, approaches using anti-idiotypic anti

- 13 046985 bodies, approaches to reduce the function of immunosuppressive cells, such as regulatory T cells, myeloid suppressor cells or IDO (indoleamine-2,3,-deoxygenase)-expressing dendritic cells, and approaches using cancer vaccines consisting of proteins or peptides derived from tumor-associated antigens such as NY-ESO-1, MAGE-3, WT1 or Her2/neu.

Thus, in a further aspect of the invention there is provided a pharmaceutical product comprising a compound of formula (I), as defined above, and an additional antitumor agent, as defined above, for the joint treatment of cancer.

In such an aspect of the invention there is provided a pharmaceutical product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, and an additional antitumor agent, as defined above, for the co-treatment of cancer.

As used herein, when the term co-treatment is used with reference to a combination treatment, it is understood that this may refer to simultaneous, separate or sequential administration. References to co-administration should be interpreted in a similar manner. In one aspect of the invention, co-treatment refers to simultaneous administration. In another aspect of the invention, co-treatment refers to separate administration. In yet another aspect of the invention, co-treatment refers to sequential administration. When administration is sequential or separate, the dwell time before administration of the second component should not be such that the advantage of the effect resulting from the use of the combination is lost. Thus, in one embodiment, sequential administration includes administration of each component of the combination over a period of 11 days. In another embodiment, this period is 10 days. In yet another embodiment, this period is 9 days. In yet another embodiment, this period is 8 days. In yet another embodiment, this period is 7 days. In yet another embodiment, this period is 6 days. In yet another embodiment, this period is 5 days. In yet another embodiment, this period is 4 days. In yet another embodiment, this period is 3 days. In yet another embodiment, this period is 2 days. In yet another embodiment, this period is 24 hours. In yet another embodiment, this period is 12 hours.

Thus, one embodiment of the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, and an additional antitumor agent for the co-treatment of cancer.

One embodiment of the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined herein, and an additional antitumor agent for the simultaneous, separate or sequential treatment of cancer.

In one embodiment, there is provided a method of producing an anticancer effect in a warm-blooded animal, such as a human, in need of such treatment, comprising administering to said animal a compound of formula (I) or a pharmaceutically acceptable salt thereof and co-administrating an additional anticancer agent to said animal, wherein amounts of the compound of formula ( I) or a pharmaceutically acceptable salt thereof and an additional antitumor agent are collectively effective in producing an anticancer effect.

In one embodiment, there is provided a method of producing an anticancer effect in a warm-blooded animal, such as a human, in need of such treatment, comprising administering to said animal a compound of formula (I) or a pharmaceutically acceptable salt thereof and simultaneously, separately or sequentially administering an additional antitumor agent to said animal, wherein amounts of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an additional antitumor agent are collectively effective in producing an anticancer effect.

In the manufacture of medicinal compositions, it is important for the drug substance to be in a form in which it can be conveniently handled and processed. This is important not only from the point of view of carrying out an industrially acceptable production method, but also from the point of view of the subsequent production of pharmaceutical preparations (eg, oral dosage forms such as tablets) containing the active compound.

The different physical properties of the crystalline forms relative to each other and relative to the non-crystalline state can have a significant impact on the chemical and pharmaceutical processing of a compound, especially when the compound is prepared or used on an industrial scale.

In addition, in the manufacture of oral drug compositions, it is important that a reliable and reproducible plasma concentration profile of the drug is achieved after administration to the patient. Interpatient variability in the absorption profile of a drug in the stomach, intestine, or bloodstream may affect the safety and effectiveness of the drug.

Chemical stability, solid state stability and shelf life of the active ingredients are also very important factors. The drug substance and compositions containing it must be capable of maintaining effectiveness for acceptable periods of time without adverse effects.

- 14 046985 significant change in the physicochemical characteristics of the active component (for example, its chemical composition, density, hygroscopicity and solubility).

Moreover, the ability to offer the drug in a form that is as chemically pure as possible is important.

Amorphous materials can present problems in this regard. For example, such materials tend to be difficult to process and manufacture, exhibit unreliable solubility, and are often found to be unstable and chemically contaminated.

One skilled in the art will appreciate that if a drug can be easily obtained in a stable crystalline form, the above problems can be solved.

Thus, in the manufacture of industrially suitable and pharmaceutically acceptable drug compositions, it is important to provide, where possible, the drug in crystalline and stable form.

It should be noted, however, that this goal is not always achievable. Indeed, it is usually impossible to predict from molecular structure alone what the crystallization behavior of a compound will be, either on its own or in salt form. This can only be determined empirically.

In a further aspect of the invention, certain compounds and their salts can be obtained in crystalline forms. These crystalline forms can be characterized as specific polymorphic forms. When the present invention is said to be in crystalline form, the degree of crystallinity is preferably greater than about 60%, more preferably greater than about 80%, preferably greater than about 90%, and more preferably greater than about 95%. Most preferably, the degree of crystallinity is greater than about 98%.

The particular solid forms described herein exhibit X-ray powder diffraction patterns substantially the same as the X-ray powder diffraction patterns shown in the figures and have individual 2-theta values as shown in the tables included herein. It should be understood that 2-theta powder X-ray diffraction pattern values may vary slightly from equipment to equipment or from sample to sample, and such recorded values should not be interpreted as absolute values.

It is known that an X-ray powder diffraction pattern can be obtained having one or more measurement errors depending on the measurement conditions (such as the equipment or apparatus used). For example, it is generally known that the intensities in the X-ray powder diffraction pattern can deviate depending on the measurement conditions. Thus, it should be understood that the solid forms of the present invention are not limited to crystals that produce powder x-ray diffraction patterns identical to the powder x-ray diffraction patterns shown in the figures, and any crystals that produce powder x-ray diffraction patterns substantially the same as those shown in the figures are included within the scope of the present invention. A person skilled in the art of X-ray powder diffraction is able to evaluate the essentially similarity of X-ray powder diffraction patterns.

Those skilled in the field of X-ray powder diffraction understand that the relative intensity of the peaks can be influenced, for example, by grain sizes above 30 μm, as well as non-unitary relationships that can affect the analysis of samples. Those skilled in the art also recognize that the position of the reflections can be influenced by the exact height at which the sample is placed in the diffractometer, as well as the calibration of the diffractometer zero. The flatness of the sample surface may also have a small influence. Therefore, the diffraction pattern data reported should not be taken as absolute values (Jenkins, R & Snyder, R.L. Introduction to X-Ray Powder Diffractometry, John Wiley & Sons, 1996; Bunn, C.W. (1948), Chemical Crystallography, Clarendon Press, London; Klug , H.P. & Alexander, L.E. (1974), X-Ray Diffraction Procedures).

In general, the measurement error of the diffraction angle in an X-ray powder diffraction pattern is approximately ±0.2° 2-theta, and this degree of measurement error should be taken into account when considering the X-ray powder diffraction patterns in the figures, as well as when reading the data contained in tables included in this description. Moreover, it should be understood that intensities may deviate depending on experimental conditions and sample preparation (preferred orientation).

In this specification, N(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide is designated as Compound X. Compound X initially formed was found to be an amorphous solid. Several useful crystalline polymorphic forms have thus been obtained using the conditions described here in the experimental section. In all solid form embodiments described herein, the peaks in the powder x-ray diffraction patterns are measured using CuKa radiation.

Polymorphic Form A of Compound X.

- 15 046985

Thus, in a further aspect of the invention, there is provided polymorphic form A of Compound X. This polymorphic form can be characterized by giving at least one of the following 2θ values measured using CuKa radiation: 7.8 and 21.8.

Polymorph Form A of Compound X exhibits a powder X-ray diffraction pattern substantially as shown in FIG. 1.

The ten powder X-ray diffraction peaks for this polymorph [2-theta angle (2θ), intensity (%)] are 7.8 (100%), 21.8 (73.4%), 13.3 (59 .4%), 6.6 (49.5%), 23.9 (40.5%), 9.6 (38.1%), 14.5 (35.3%), 15.6 (33 .2%), 22.7 (31.2%) and 19.1 (29.8%).

The present invention provides polymorph Form A of Compound X which has a powder x-ray diffraction pattern with at least one characteristic peak at a 2-theta value of approximately 7.8°.

The present invention provides polymorph Form A of Compound X which has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of approximately 21.8°.

The present invention provides polymorph Form A of Compound X which has a powder X-ray diffraction pattern with at least two characteristic peaks at 2-theta values of approximately 7.8 and 21.8°.

The present invention provides polymorph Form A of Compound X which has a powder X-ray diffraction pattern with characteristic peaks at 2-theta values of approximately 7.8, 21.8, 13.3, 6.6, 23.9, 9 .6, 14.5, 15.6, 22.7 and 19.1°.

The present invention provides polymorph Form A of Compound X which has a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern shown in FIG. 1.

The present invention provides polymorph Form A of Compound X which has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of 7.8 ± 0.2° 2-theta.

The present invention provides polymorph Form A of Compound X which has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of 21.8 ± 0.2° 2-theta.

The present invention provides polymorph Form A of Compound X which has a powder X-ray diffraction pattern with at least two characteristic peaks at 2-theta values of 7.8 and 21.8°, where these values may differ by ±0. 2° 2-theta.

The present invention provides polymorph Form A of Compound X which has a powder X-ray diffraction pattern with characteristic peaks at 2-theta values of 7.8, 21.8, 13.3, 6.6, 23.9, 9. 6, 14.5, 15.6, 22.7 and 19.1°, where the stated values may differ by ±0.2° 2-theta.

Polymorphic form B of Compound X.

In a further aspect of the invention there is provided a polymorphic form B of Compound X. This polymorphic form can be characterized by giving at least one of the following 2θ values measured using CuKa radiation: 9.3 and 23.4.

Polymorph Form B of Compound X exhibits a powder X-ray diffraction pattern substantially as shown in FIG. 3.

The ten powder X-ray diffraction peaks for this polymorph [2-theta angle (2θ), intensity (%)] are 9.3 (100%), 23.4 (75.0%), 10.5 (63 .6%), 17.7 (54.3%), 21.0 (48.1%), 16.1 (46.4%), 26.1 (44.2%), 18.6 (41 .8%), 26.7 (32.2%) and 20.6 (30.9%).

The present invention provides a Form B polymorph of Compound X that has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of approximately 9.3°.

The present invention provides a Form B polymorph of Compound X which has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of approximately 23.4°.

The present invention provides a Form B polymorph of Compound X that has a powder X-ray diffraction pattern with at least two characteristic peaks at 2-theta values of approximately 9.3 and 23.4°.

The present invention provides polymorph Form B of Compound X which has a powder X-ray diffraction pattern with characteristic peaks at 2-theta values of approximately 9.3, 23.4, 10.5, 17.7, 21.0, 16 ,1, 26.1, 18.6, 26.7 and 20.6°.

The present invention provides a Form B polymorph of Compound X which has a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern shown in FIG. 3.

- 16 046985

The present invention provides a Form B polymorph of Compound X which has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of 9.3 ± 0.2° 2-theta.

The present invention provides a Form B polymorph of Compound X which has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of 23.4 ± 0.2° 2-theta.

The present invention provides polymorph Form B of Compound X which has a powder X-ray diffraction pattern with at least two characteristic peaks at 2-theta values of 9.3 and 23.4°, where these values may differ by ±0. 2° 2-theta.

The present invention provides polymorph Form B of Compound X which has a powder X-ray diffraction pattern with characteristic peaks at 2-theta values of 9.3, 23.4, 10.5, 17.7, 21.0, 16. 1, 26.1, 18.6, 26.7 and 20.6°, where the stated values may differ by ±0.2° 2-theta.

Polymorphic form C of Compound X.

In a further aspect of the invention there is provided a polymorphic form C of Compound X. This polymorphic form can be characterized by giving at least one of the following 2θ values measured using CuKa radiation: 6.0 and 11.3.

Polymorph Form C of Compound X exhibits a powder X-ray diffraction pattern substantially as shown in FIG. 5.

The ten powder X-ray diffraction peaks for this polymorph [2-theta angle (2θ), intensity (%)] are 6.0 (100%), 11.3 (58.2%), 7.5 (40 .5%), 10.3 (21.9%), 12.0 (20.1%), 24.9 (19.4%), 13.0 (16.9%), 14.5 (13 .5%), 16.5 (13.5%) and 18.3 (11.8%).

The present invention provides a Form C polymorph of Compound X that has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of approximately 6.0°.

The present invention provides a Form C polymorph of Compound X that has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of approximately 11.3°.

The present invention provides a Form C polymorph of Compound X that has a powder X-ray diffraction pattern with at least two characteristic peaks at 2-theta values of approximately 6.0 and 11.3°.

The present invention provides a Form C polymorph of Compound X which has a powder X-ray diffraction pattern with characteristic peaks at 2-theta values of approximately 6.0, 11.3, 7.5, 10.3, 12.0, 24 .9, 13.0, 14.5, 16.5 and 18.3°.

The present invention provides polymorph Form C of Compound X which has a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern shown in FIG. 5.

The present invention provides a Form C polymorph of Compound X which has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of 6.0 ± 0.2° 2-theta.

The present invention provides a Form C polymorph of Compound X which has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of 11.3 ± 0.2° 2-theta.

The present invention provides a Form C polymorph of Compound X which has a powder X-ray diffraction pattern with at least two characteristic peaks at 2-theta values of 6.0 and 11.3°, where these values may differ by ±0. 2° 2-theta.

The present invention provides a Form C polymorph of Compound X which has a powder X-ray diffraction pattern with characteristic peaks at 2-theta values of 6.0, 11.3, 7.5, 10.3, 12.0, 24, 9, 13.0, 14.5, 16.5 and 18.3°, where the stated values may differ by ±0.2° 2-theta.

Polymorphic Form D of Compound X.

In a further aspect of the invention there is provided polymorph Form D of Compound X, which is believed to be a monohydrate crystalline form. This polymorph can be characterized as having at least one of the following 2θ values measured using CuKa radiation: 9.3 and 10.5.

Polymorph Form D of Compound X exhibits a powder X-ray diffraction pattern substantially as shown in FIG. 7.

The ten powder X-ray diffraction peaks for this polymorph [2-theta angle (2θ), intensity (%)] are 9.3 (100%), 10.5 (90.6%), 16.1 (75 ,8%),

- 17 046985

26.1 (75.2%), 21.0 (70.9%), 20.6 (56.9%), 16.8 (56.5%), 17.7 (53.3%), 14.7 (41.3%) and 9.7 (38.3%).

The present invention provides a Form D polymorph of Compound X that has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of approximately 9.3°.

The present invention provides a Form D polymorph of Compound X that has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of approximately 10.5°.

The present invention provides a Form D polymorph of Compound X that has a powder X-ray diffraction pattern with at least two characteristic peaks at 2-theta values of approximately 9.3 and 10.5°.

The present invention provides a Form D polymorph of Compound X which has a powder X-ray diffraction pattern with characteristic peaks at 2-theta values of approximately 9.3, 10.5, 16.1, 26.1, 21.0, 20 .6, 16.8, 17.7, 14.7 and 9.7°.

The present invention provides a polymorph Form D of Compound X which has a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern shown in FIG. 7.

The present invention provides a polymorphic Form D of Compound X which has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of 9.3 ± 0.2° 2-theta.

The present invention provides a polymorphic Form D of Compound X which has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of 10.5 ± 0.2° 2-theta.

The present invention provides a polymorphic Form D of Compound X which has a powder X-ray diffraction pattern with at least two characteristic peaks at 2-theta values of 9.3 and 10.5°, where these values may differ by ±0. 2° 2-theta.

The present invention provides a polymorphic Form D of Compound X which has a powder X-ray diffraction pattern with characteristic peaks at 2-theta values of 9.3, 10.5, 16.1, 26.1, 21.0, 20. 6, 16.8, 17.7, 14.7 and 9.7°, where the stated values may differ by ±0.2° 2-theta.

Polymorphic form E of Compound X.

In a further aspect of the invention, there is provided polymorph Form E of Compound X, which is believed to be the crystalline 1,25-stoichiometric hydrate form of Compound X. This polymorph may be characterized by giving at least one of the following 2θ values measured using CuKa radiation: 9.2 and 22.9.

Polymorph Form E of Compound X exhibits a powder X-ray diffraction pattern substantially as shown in FIG. 10.

The ten powder X-ray diffraction peaks for this polymorph [2-theta angle (2θ), intensity (%)] are: 9.2 (100%), 22.9 (84.0%), 14.6 ( 80.3%), 12.7 (77.8%), 16.5 (66.4%), 26.9 (60.3%), 9.7 (95.6%), 14.0 ( 52.3%), 10.4 (49.9%) and 19.5 (48.3%).

The present invention provides a Form E polymorph of Compound X that has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of approximately 9.2°.

The present invention provides a Form E polymorph of Compound X that has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of approximately 22.9°.

The present invention provides a Form E polymorph of Compound X that has a powder X-ray diffraction pattern with at least two characteristic peaks at 2-theta values of approximately 9.2 and 22.9°.

The present invention provides a polymorphic Form E of Compound X which has a powder X-ray diffraction pattern with characteristic peaks at 2-theta values of approximately 9.2, 22.9, 14.6, 12.7, 16.5, 26 .9, 9.7, 14.0, 10.4 and 19.5°.

The present invention provides polymorph Form E of Compound X which has a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern shown in FIG. 10.

The present invention provides a polymorphic Form E of Compound X which has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of 9.2 ± 0.2° 2-theta.

The present invention provides a polymorphic Form E of Compound X which has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of 22.9° ±0.2° 2-theta.

- 18 046985

The present invention provides a polymorphic Form E of Compound X which has a powder X-ray diffraction pattern with at least two characteristic peaks at 2-theta values of 9.2 and 22.9°, where these values may differ by ±0. 2° 2-theta.

The present invention provides a polymorphic Form E of Compound X which has a powder X-ray diffraction pattern with characteristic peaks at 2-theta values of 9.2, 22.9, 14.6, 12.7, 16.5, 26. 9, 9.7, 14.0, 10.4 and 19.5°, where the stated values may differ by ±0.2° 2-theta.

Polymorphic form F of Compound X.

In a further aspect of the invention, there is provided polymorph Form F of Compound X, which is believed to be the 0.25 stoichiometric hydrate form of Compound X. This polymorph may be characterized as having at least one of the following 2θ values measured using CuKa radiation: 18.7 and 8.99.

Polymorph Form F of Compound X exhibits a powder X-ray diffraction pattern substantially as shown in FIG. 13.

The ten powder X-ray diffraction peaks for this polymorph [2-theta angle (2θ), intensity (%)] are: 18.7 (100%), 8.9 (87.7%), 15.1 ( 80.3%), 25.4 (74.6%), 14.5 (72.3%), 22.9 (69.6%), 9.9 (51.1%), 28.2 ( 42.0%), 8.2 (24.2%) and 11.9 (22.3%).

The present invention provides a polymorphic Form F of Compound X that has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of approximately 18.7°.

The present invention provides a polymorphic form F of Compound X that has a powder x-ray diffraction pattern with at least one characteristic peak at a 2-theta value of approximately 8.9°.

The present invention provides a polymorphic Form F of Compound X that has a powder X-ray diffraction pattern with at least two characteristic peaks at 2-theta values of approximately 18.7 and 8.9°.

The present invention provides a polymorphic Form F of Compound X which has a powder X-ray diffraction pattern with characteristic peaks at

2-theta, approximately equal to 18.7, 8.9, 15.1, 25.4, 14.5, 22.9, 9.9, 28.2, 8.2 and 11.9°.

The present invention provides a polymorph Form F of Compound X which has a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern shown in FIG. 13.

The present invention provides a polymorphic Form F of Compound X which has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of 18.7 ± 0.2° 2-theta.

The present invention provides a polymorphic Form F of Compound X which has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of 8.9 ± 0.2° 2-theta.

The present invention provides a polymorphic Form F of Compound X which has a powder X-ray diffraction pattern with at least two characteristic peaks at 2-theta values of 18.7 and 8.9°, where these values may differ by ±0. 2° 2-theta.

The present invention provides a polymorphic Form F of Compound X which has a powder X-ray diffraction pattern with characteristic peaks at 2-theta values of 18.7, 8.9, 15.1,25.4, 14.5,22. 9, 9.9, 28.2, 8.2 and 11.9°, where the stated values may differ by ±0.2° 2-theta.

Polymorphic form K of Compound X.

In a further aspect of the invention, a polymorphic form K of Compound X is provided. This polymorphic form can be characterized as having at least one of the following 2θ values measured using CuKa radiation: 8.4 and 9.7.

Polymorph Form K of Compound X exhibits a powder X-ray diffraction pattern substantially as shown in FIG. 16.

The ten powder X-ray diffraction peaks for this polymorph [2-theta angle (2θ), intensity (%)] are: 8.4 (100%), 9.7 (37.7%), 12.2 ( 32.4%), 15.1 (25.2%), 24.7 (20.7%), 9.0 (16.8%), 21.9 (13.9%), 19.5 ( 13.9%), 24.2 (13.8%) and 18.3 (11.8%).

The present invention provides a Form K polymorph of Compound X that has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of approximately 8.4°.

The present invention provides a polymorphic Form K of Compound X which has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of approximately 9.7°.

The present invention provides a polymorph Form K of Compound X that has a powder X-ray diffraction pattern with at least two characteristic peaks at 2-theta values of approximately 8.4 and 9.7°.

The present invention provides a polymorphic Form K of Compound X which has a powder X-ray diffraction pattern with characteristic peaks at 2-theta values of approximately 8.4, 9.7, 12.2, 15.1, 24.7, 9 ,0, 21.9, 19.5, 24.2 and 18.3°.

The present invention provides a Form K polymorph of Compound X that has a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern shown in FIG. 16.

The present invention provides a polymorphic Form K of Compound X which has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of 8.4° ±2° 2-theta.

The present invention provides a polymorphic Form K of Compound X which has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of 9.7 ± 0.2° 2-theta.

The present invention provides a polymorphic Form K of Compound X which has a powder X-ray diffraction pattern with at least two characteristic peaks at 2-theta values of 8.4 and 9.7°, where these values may differ by ±0. 2° 2-theta.

The present invention provides a polymorphic Form K of Compound X which has a powder X-ray diffraction pattern with characteristic peaks at 2-theta values of 8.4, 9.7, 12.2, 15.1, 24.7, 9. 0, 21.9, 19.5, 24.2 and 18.3°, where specified values may differ by ±0.2° 2-theta.

In this specification, the mesylate salt of N(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide is designated as Mesylate Salt Y.

Polymorphic form A of Mesylate Salt Y.

In a further aspect of the invention, Mesylate Salt Y polymorph Form A is provided. This polymorph may be characterized as having at least one of the following 2θ values measured using CuKa radiation: 5.6 and 6.5.

Polymorph Form A of Mesylate Salt Y is characterized by a powder X-ray diffraction pattern essentially as shown in FIG. 18.

The ten powder X-ray diffraction peaks for this polymorph [2-theta angle (2θ), intensity (%)] are: 5.6 (100%), 6.5 (66.7%), 10.2 ( 97.2%), 21.0 (96.2%), 13.5 (91.7%), 22.7 (89.6%), 19.3 (80.6%), 27.3 ( 75.7%), 15.7 (71.2%) and 19.9 (66.7%).

The present invention provides polymorph Form A of Mesylate Salt Y which has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of approximately 5.6°.

The present invention provides polymorph Form A of Mesylate Salt Y which has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of approximately 6.5°.

The present invention provides polymorph Form A of Mesylate Salt Y which has a powder X-ray diffraction pattern with at least two characteristic peaks at 2-theta values of approximately 5.6 and 6.5°.

The present invention provides polymorph Form A of Mesylate Salt Y which has a powder X-ray diffraction pattern with characteristic peaks at 2-theta values of approximately 5.6, 6.5, 10.2, 21.0, 13.5, 22.7, 19.3, 27.3, 15.7 and 19.9°.

The present invention provides polymorph Form A of Mesylate Salt Y which has a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern shown in FIG. 18.

The present invention provides polymorph Form A of Mesylate Salt Y which has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of 5.6 ± 0.2° 2-theta.

The present invention provides polymorph Form A of Mesylate Salt Y which has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of 6.5 ± 0.2° 2-theta.

The present invention provides polymorph Form A of Mesylate Salt Y which has a powder X-ray diffraction pattern with at least two characteristic peaks at 2-theta values of 5.6 and 6.5°, where these values may differ by ±0 ,2° 2-theta.

According to the present invention, there is provided a polymorphic form A of Mesylate Salt Y, which

- 20 046985 rai has an X-ray powder diffraction pattern with characteristic peaks at 2-theta values of 5.6, 6.5, 10.2, 21.0, 13.5, 22.7, 19.3, 27 ,3, 15.7 and 19.9°, where the indicated values may differ by ±0.2° 2-theta.

Polymorphic form B of Mesylate Salt Y.

In a further aspect of the invention there is provided a polymorph form B of Mesylate Salt Y. This polymorph form can be characterized as having at least one of the following 2θ values measured using CuKa radiation: 7.2 and 8.6.

Polymorph Form B of Mesylate Salt Y is characterized by a powder X-ray diffraction pattern essentially as shown in FIG. 20.

The ten X-ray powder diffraction peaks for this polymorphic form [2-theta angle (2θ), intensity (%)] are: 7.2 (50.2%), 8.6 (55.2%), 15. 3 (100%), 10.4 (92.6%), 25.7 (74.0%), 26.1 (63.9%), 16.4 (55.2%), 9.5 ( 47.5%), 22.1 (46.9%) and 18.8 (47.7%).

The present invention provides polymorph Form B of Mesylate Salt Y which has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of approximately 7.2°.

The present invention provides polymorph Form B of Mesylate Salt Y which has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of approximately 8.6°.

The present invention provides polymorph Form B of Mesylate Salt Y which has a powder X-ray diffraction pattern with at least two characteristic peaks at 2-theta values of approximately 7.2 and 8.6°.

The present invention provides polymorph Form B of Mesylate Salt Y which has a powder X-ray diffraction pattern with characteristic peaks at 2-theta values of approximately 7.2, 8.6, 15.3, 10.4, 25.7, 26.1, 16.4, 9.5, 22.1 and 18.8°.

The present invention provides polymorph Form B of Mesylate Salt Y which has a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern shown in FIG. 20.

The present invention provides polymorph Form B of Mesylate Salt Y which has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of 7.2 ± 0.2° 2-theta.

The present invention provides polymorph Form B of Mesylate Salt Y which has a powder X-ray diffraction pattern with at least one characteristic peak at a 2-theta value of 8.6 ± 0.2° 2-theta.

The present invention provides polymorph Form B of Mesylate Salt Y which has a powder X-ray diffraction pattern with at least two characteristic peaks at 2-theta values of 7.2 and 8.6°, where these values may differ by ±0 ,2° 2-theta.

The present invention provides polymorph Form B of Mesylate Salt Y which has a powder X-ray diffraction pattern with characteristic peaks at 2-theta values of 7.2, 8.6, 15.3, 10.4, 25.7, 26 ,1, 16.4, 9.5, 22.1 and 18.8°, where the specified values may differ by ±0.2° 2-theta.

List of figures

All figures refer to the solid forms of the compound >{2-{2-dimethylaminoethyl-methylamino}-4methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2- enamide (Compound X) or its mesylate salt when indicated (Mesylate salt Y).

Fig. 1. X-ray diffraction pattern on Form A powder.

Fig. 2. DSC thermogram of form A.

Fig. 3. X-ray diffraction pattern on form B powder.

Fig. 4. DSC thermogram of form B.

Fig. 5. X-ray diffraction pattern on form C powder.

Fig. 6. DSC thermogram of form C.

Fig. 7. X-ray diffraction pattern of form D (monohydrate) powder.

Fig. 8. DSC thermogram of form D monohydrate.

Fig. 9. TGA thermogram of form D monohydrate.

Fig. 10. X-ray diffraction pattern of form E powder (hydrated form).

Fig. 11. DSC thermogram of form E (hydrated form).

Fig. 12. TGA thermogram of form E (hydrated form).

Fig. 13. X-ray diffraction pattern of form F (hydrated form) powder.

Fig. 14. DSC thermogram of form F (hydrated form).

Fig. 15. TGA thermogram of Form F (hydrated form).

Fig. 16. X-ray diffraction pattern from form K powder.

- 21 046985

Fig. 17. DSC thermogram of form K.

Fig. 18. X-ray diffraction pattern of powder form A of the mesylate salt.

Fig. 19. DSC thermogram of form A of mesylate salt.

Fig. 20. X-ray diffraction pattern of powder form B of mesylate salt.

Fig. 21. DSC thermogram of form B of mesylate salt.

Methods of chemical synthesis and biological analysis.

The following abbreviations may be used:

THF means tetrahydrofuran;

DIPEA means diisopropylethylamine;

sat. means saturated aqueous solution;

FCC stands for flash silica column chromatography;

TFA means trifluoroacetic acid;

k.t. means room temperature;

DMF means ^^dimethylformamide;

DMSO means dimethyl sulfoxide;

DMA means ^^dimethylacetamide;

EtOAc means ethyl acetate;

h means hour(s);

Proton NMR: (1H NMR) was determined using deuterated dimethyl sulfoxide at 400 or 500 MHz at approximately 20-30°C unless otherwise noted.

Standard NMR abbreviations are used (s means singlet; d means doublet; dd means doublet of doublets; t means triplet; q means quartet; p means pentet; m means multiplet; br means broad; and so on).

When iron is mentioned as a reactant, it is iron powder, 325 mesh and reduced hydrogen. The assay values reported (µM) for this example are the concentrations at which 50% inhibition is observed (IC ₅₀ ). X-ray powder diffraction (XRPD) was performed using Broker D4 equipment. The X-ray powder diffraction pattern was determined by mounting a sample of crystalline material on a Bruker single crystal silicon wafer (SSC) and smoothing the sample into a thin layer using a glass slide. The sample was rotated at 30 rpm (to improve statistical calculations) and irradiated with X-rays generated by a copper long-fine focus tube operating at 40 kV and 40 mA, with a wavelength of 1.5418 Angstrom (CuKa radiation). The collimated X-ray beam from the source was passed through an automatically controlled slit divergence setup at V20 (20 mm path length) and the reflected radiation was directed through a 5.89 mm anti-scatter slit and a 9.55 mm detector slit. The sample was exposed for 0.03 s at 2-theta increments of 0.00570° (continuous scan mode) over a 2-theta angle range of 2 to 40° in theta-theta mode. The run time was 3 minutes 36 seconds. This instrument was equipped with a position change detector (Lynxeye). Control and data collection were carried out using a Dell Optiplex 686 NT 4.0 Workstation running with the Diffrac+ software product. Differential scanning calorimetry (DSC) was carried out using a TA Instruments Q1000 differential scanning calorimeter. Typically, less than 5 mg of material placed in a standard aluminum crucible with a lid was heated over a temperature range of 25 to 300°C at a constant heating rate of 10°C/min. Nitrogen gas purge was used at a flow rate of 50 mL/min. Any crystalline form that produces XRPD diffraction patterns or DSC thermograms substantially identical to those described herein is within the scope of the present inventions. One skilled in the art will be able to determine the substantially similarities between diffraction patterns and thermograms.

Assay 1. Analysis of cellular phosphorylation of EGFR with deletion in exon 19 (activating single mutant).

The human lung cell line PC9 (EGFR with exon 19 deletion) was obtained from the American Type Culture Collection. PC9 was maintained in RPMI 1640 medium containing 10% fetal bovine serum and 2 mM glutamine. Cells were grown in a humidified incubator at 37°C with 5% CO2. Assays to measure cellular phosphorylation of endogenous p-EGFR in cell lysates were performed according to the protocol described in R&D Systems DuoSet IC Human Phospho-EGF RELISA (R&D Systems, catalog # DYC1095).

µl of cells were seeded (10,000 cells/well) in growth medium in black 384-well Corning clear-bottom plates and incubated at 37°C with 5% CO2 overnight. Cells were acoustically piped using Echo 555, with compounds serially diluted in 100% DMSO. The plates were incubated for an additional 2 h, then the medium was aspirated and 40 μl of 1x lysis buffer was added to each well. Greiner high-binding black 384-well plates were coated with immobilized antibody and then blocked with 3% BSA. After block removal

- 22 046985 µl of lysate was transferred to black 384-well high binding Greiner plates and incubated for 2 hours. After aspiration and washing of the plates with PBS, 20 µl of detection antibody was added and incubated for 2 hours. After aspiration and washing of the plates with PBS, 20 µl was added fluorogenic peroxidase substrate QuantaBlu (Thermo Fisher Scientific, catalog number 15169) and incubated for 1 hour. 20 μl of QuantaBlu blocking solution was added to the plates, and fluorescence was read on an Envision plate reader using an excitation wavelength of 352 nm and an emission wavelength 460 nm. Data obtained from each compound were entered into a software package (such as Origin) for analytical curve fitting. From these data, IC ₅₀ values were obtained, determined by calculating the concentration of the compound required to obtain 50% effect.

Assay 2: L858R/T790M EGFR Cellular Phosphorylation Assay (double mutant).

Human lung cell lines NCI-H1975 were obtained from the American Type Culture Collection. NCI-H1975 was maintained in RPMI 1640 medium containing 10% fetal bovine serum and 2 mM glutamine. Cells were grown in a humidified incubator at 37°C with 5% CO2. Assays to measure cellular phosphorylation of endogenous p-EGFR in cell lysates were performed according to the protocol described in R&D Systems DuoSet IC Human Phospho-EGF R ELISA (R&D Systems, catalog #DYC1095). 40 μl of cells were seeded (10,000 cells/well) into growth medium in black 384-well Corning clear-bottom plates and incubated at 37°C with 5% CO ₂ overnight. Cells were acoustically piped using Echo 555, with compounds serially diluted in 100% DMSO. The plates were incubated for an additional 2 h, then the medium was aspirated and 40 μl of 1x lysis buffer was added to each well. Greiner high-binding black 384-well plates were coated with immobilized antibody and then blocked with 3% BSA. After block removal, 15 μl of lysate was transferred to black 384-well high-binding Greiner plates and incubated for 2 h. After aspiration and washing of the plates with PBS, 20 μl of detection antibody was added and incubated for 2 h. After aspiration and washing of the plates with PBS, 20 µl of detection antibody and incubated for 2 hours. After aspirating and washing the plates with PBS, 20 µl of QuantaBlu fluorogenic peroxidase substrate (Thermo Fisher Scientific, catalog number 15169) was added and incubated for 1 hour. 20 µl of QuantaBlu blocking solution was added to the plates. and fluorescence was read on an Envision plate reader using an excitation wavelength of 352 nm and an emission wavelength of 460 nm. Data obtained from each compound were entered into a software package (such as Origin) for analytical curve fitting. From these data, IC ₅₀ values were obtained, determined by calculating the concentration of the compound required to obtain 50% effect.

Assay 3: Cellular Phosphorylation Analysis of Wild-Type EGFR The human colon cell line LoVo was obtained from the American Type Culture Collection. LoVo was maintained in RPMI 1640 medium containing 3% depleted fetal bovine serum and 2 mM glutamine. Cells were grown in a humidified incubator at 37°C with 5% CO2. Assays to measure cellular phosphorylation of endogenous p-EGFR in cell lysates were performed according to the protocol described in the R&D Systems DuoSet 1C Human Phospho-EGF R ELISA (R&D Systems, catalog # DYC1095). 40 μl of cells were seeded (15,000 cells/well) in growth medium in black 384-well Corning clear-bottom plates and incubated at 37°C with 5% CO ₂ overnight. Cells were acoustically piped using Echo 555, with compounds serially diluted in 100% DMSO. The plates were incubated for an additional 2 h, then stimulated with 100 ng/ml for 10 min and the medium was aspirated and 40 μl of 1x lysis buffer was added to each well. Greiner high-binding black 384-well plates were coated with immobilized antibody and then blocked with 3% BSA. After block removal, 15 μl of lysate was transferred to black 384-well high-binding Greiner plates and incubated for 2 h. After aspiration and washing of the plates with PBS, 20 μl of detection antibody was added and incubated for 2 h. After aspiration and washing of the plates, PBS was added 20 μl of QuantaBlu fluorogenic peroxidase substrate (Thermo Fisher Scientific, catalog number 15169) and incubated for 1 h. 20 μl of QuantaBlu blocking solution was added to the plates, and fluorescence was read on an Envision plate reader using an excitation wavelength of 352 nm and radiation waves 460 nm. Data obtained from each compound were entered into a software package (such as Origin) for analytical curve fitting. From these data, IC ₅₀ values were obtained, determined by calculating the concentration of the compound required to obtain 50% effect.

Assay data (µM) for the example compounds of this application are shown in the table below. Although the analysis data are reported to a certain number of significant figures, this should not be taken to represent that the data is defined to that number of significant figures.

- 23 046985

Example No. Analysis 1 Analysis 2 Analysis 3 1 0.007614 0.004956 0.4744 2 0.001291 0.001504 0.04122 3 0.01054 0.01549 0.5222 4 0.01273 0.0016 0.5099 5 0.02059 0.003402 0.8225 6 0.002183 0.0006695 0.1959 7 0.003262 0.0006825 0.1606 8 0.02239 0.005481 1D7 9 0.009959 0.002818 0.8744 10 0.07377 0.03998 8,427 AND 0.02854 0.01871 1,599 12 0.03613 0.005821 1,393 13 0.1388 0.01926 11.91 14 0.05328 0.01912 12.48 15 0.01399 0.05524 1.067 16 0.1437 0.07052 >18.92 17 0.02344 0.005644 0.772 18 0.06644 0.03138 2,696 19 0.002149 0.001463 0.07081 20 0.007487 0.005276 0.1929 21 0.002948 0.002339 0.1283 22 0.002137 0.001524 0.07336 23 0.01694 0.01759 3,018 24 0.001327 0.0008856 0.03567 25 0.0005811 0.000238 0.01092 26 0.002289 0.001925 0.05831 27 0.00561 0.01142 0.3177 28 0.01292 0.01144 0.4938 28A 0.01975 0.01271 1.443 29 0.001228 0.0008846 0.04652 thirty 0.07375 0.05211 1.613

- 24 046985

31 0.03746 0.00734 2,506 32 0.138 0.02378 10.53 33 0.8916 1.158 11.86 34 0.009044 0.003767 0.1526 35 0.008571 0.006772 0.2623 36 0.04329 0.03272 1.051 37 0.002112 0.001814 0.04859 38 0.005092 0.004405 0.5384 39 0.002336 0.001005 0.2484 40 0.0124 0.01477 >30 41 0.02863 0.0295 1.841 42 0.005192 0.005161 0.4542 43 0.01817 0.01055 1.34 44 0.03329 0.0256 3.64 45 0.1102 0.041 7,396 46 0.1289 0.09293 7,091 47 0.1939 0.1192 15.45 48 0.03988 0.03098 1,579 49 0.0742 0.05097 3,093 50 0.1145 0.1297 7,626 51 0.01296 0.007713 0.4622 52 0.02603 0.01501 1.4 53 0.03537 0.02824 2.638 54 0.003217 0.002803 0.1832 55 0.006433 0.002863 0.5066 56 0.04433 0.02922 3,504 57 0.006455 0.01452 0.08931 58 0.007085 0.01683 0.1786 59 0.002266 0.003021 0.02816 60 0.0146 0.04886 0.6241

Example 1. Y-{4-Metho1<ci-2-[1-methyl-3,6-dihydro-211-11iridi11-4-yl]-5-[(5-methide-4-11irazolo[1,5a] pyridin-3-ylpyrimidin-2-yl)amino]phenyl}prop-2-enamide.

Acryloyl chloride (0.331 ml, 1 M in THF, 0.33 mmol) was added dropwise to a solution of 6-methoxy-4-(1methide-1.23.6-tetra1D1dro11iridi11-4-ide)-U ¹ -[5-methide-4- (||irazodo[1.5-a]||iridi11-3-yl)||irimidi11-2yl]benzene-1,3-diamine (Intermediate 1, 146 mg, 0.33 mmol) and DIPEA (0.086 ml, 0 .50 mmol) in THF (4 ml) at -10°C for a 1-minute period under N2 atmosphere. The resulting mixture was stirred at 0°C for 15 minutes and then concentrated in vacuo. The residue was dissolved in CH ₂ Cl ₂ (5 ml) with a small amount of CH ₃ OH. This solution was then washed with sat. NaHCO ₃ (2 ml), dried (MgSO ₄ ) and then concentrated in vacuo. Purification by FCC, elution with 5-25% CH3OH in CH ₂ Cl ₂ and concentration of the appropriate fractions in vacuo resulted in a material that was dissolved in a CH ₂ Cl ₂ :7N mixture. methanolic ammonia 100:8 (1 ml) and filtered through a pad of 1 g silica. Concentrating the resulting solution gave the title compound (70 mg, 38%) as a pale orange foam.

^1H NMR: 2.27 (3H, s), 2.37 (2H, m), 2.42 (3H, s), 2.53-2.57 (2H, m), 2.97 (2H, m), 3.87 (3H, d), 5.66 ( 2Н, d), 6.14 (1H, d), 6.39 (1H, d), 6.86 (1H, s), 7.07 (1H, t), 7.42 (1H, m), 7.98 (1H, s), 8.17 (1H , s), 8.32 (1H, s), 8.48 (1H, d), 8.58 (1H, s), 8.81 (1H, d), 9.29 (1H, s); m/z: ES ⁺ MH ⁺ 496.

Example 2. No(5-{[5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-4-methoxy-2-[1-methyl-3,6dihydro-21- pyridin-4-yl]phenyl)prop-2-enamide.

Acryloyl chloride (0.217 ml, 1 M in THF, 0.22 mmol) was added dropwise to a suspension of Na-[5-chloro-4(11-indol-3-yl)pyrimidin-2-yl]-4-methoxy-6- (1-methyl-3,6-dihydro-21-pyridin-4-yl)benzene-1,3diamine (Intermediate 7, 100 mg, 0.22 mmol) and DIPEA (0.057 mL, 0.33 mmol) in T1F (3 ml) at -5°C for a 1-minute period under N ₂ atmosphere. The resulting mixture was stirred at 0°C for 15 minutes and then concentrated in vacuo. The residue was dissolved in C12Cl2 (5 ml) with a few drops of C13O1 and washed with sat. Na1CO3 (2 ml). The organic solution was then dried (MgSO4) and

- 25 046985 was loaded onto silicon dioxide in a vacuum. Purification by FCC, eluting with 5-25% CH3OH in _CH2Cl2 and concentrating the appropriate fractions in _vacuo gave a residue which was washed with CH3OH (0.3 mL) and air dried to give the title compound (37 mg, 31 %) as a beige crystalline solid.

1H NMR: 2.28 (3H, s), 2.38 (2H, m), 2.55 (2H, m), 2.98 (2H, d), 3.85 (3H, s), 5.6-5.72 (2H, m), 6.15 (1H , m), 6.41 (1H, m), 6.88 (1H, s), 7.10 (1H, t), 7.18 (1H, t), 7.47 (1H, d), 7.98 (1H, s), 8.33 (1H, s), 8.36 (1H, d), 8.42 (1H, s), 8.49 (1H, s), 9.29 (1H, s), 11.86 (1H, s); m/z: ES+MH+ 515.

Example 3. N-(5-{[4-(1H-Indol-3-yl)-5-methylpyrimidin-2-yl]αmino}-4-methoxy-2-[4-methylpiperazin-1-yl]phenyl) prop-2-enamide.

Acryloyl chloride (0.025 ml, 0.30 mmol) was added dropwise with Na-[4-(1H-indol-3-yl)-5methylpyrimidin-2-yl]-4-methoxy-6-(4-methylpiperazin-1-yl) benzene-1,3-diamine (Intermediate 12, 135 mg, 0.30 mmol) and DIPEA (0.090 ml, 0.33 mmol) in CH ₂ Cl ₂ (10 ml) and DMF (2 ml) at 0°C in an N2 atmosphere. The resulting suspension was stirred at 0°C for 2 hours, then left to warm to room temperature. The mixture was then diluted with water (15 ml) and extracted with CH ₂ Cl ₂ (40 ml). The resulting organic solution was washed with saturated Na ₂ CO ₃ (20 ml) and then with saturated brine (20 ml). The solution was then dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC, eluting with 1-5% 7 M methanol ammonia in CH ₂ Cl ₂ , gave the crude product. Additional preparative HPLC purification (Waters SunFire column, 5 µm silica, 19 mm diameter, 100 mm length) eluting with mixtures of decreasing polarity water (containing 0.1% formic acid) and CH ₃ CN followed by HPLC (Waters XBridge column Prep C18 OBD, silica 5 µm, diameter 19 mm, length 100 mm) eluting with decreasing polarity mixtures of water (containing 1% NH3) and CH3CN gave the title compound (23 mg, 15%) as a white solid.

^1H NMR: 2.26 (3H, s), 2.37 (3H, s), 2.48-2.57 (4H, m), 2.87 (4H, t), 3.84 (3H, s), 5.70 (1H, d), 6.18 ( 1H, dd), 6.59 (1H, dd), 6.87 (1H, s), 7.05 (1H, dd), 7.15 (1H, t), 7.44 (1H, d), 7.83 (1H, s), 7.98 (1H , d), 8.22 (1H, s), 8.34 (1H, d), 8.49 (1H, s), 8.97 (1H, s), 11.68 (1H, s); m/z: ES ⁺ MH ⁺ 498.60.

Example 4. N-{5-[(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-2-[(3R)-3dimethylaminopyrrolidin-1 -yl] -4-methoxyphenyl}prop-2-enamide.

A solution of acryloyl chloride (0.042 ml, 0.51 mmol) in CH ₂ Cl ₂ (1 ml) was added dropwise to a mixture of N-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2- yl)-4-[(3R)-3-dimethylamino-pyrrolidin-1-yl]-6methoxybenzene-1,3-diamine (Intermediate 18, 245 mg, 0.51 mmol) and DIPEA (0.097 ml, 0.56 mmol) in CH2Cl2 (10 ml), which was cooled in an ice/water bath. The mixture was stirred for 2 hours and then washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. As a result of purification by FCC, eluting with 2% 7N. methanolic ammonia in CH2Cl2, a foam was obtained after concentration in vacuo. This foam was triturated using CH ₂ Cl ₂ and diethyl ether and the resulting solid was collected by filtration and dried to give the title compound (157 mg, 58%) as a yellow solid.

1H NMR: 1.68-1.83 (1H, m), 2.05-2.16 (1H, m), 2.18 (6H, s), 2.64-2.76 (1H, m), 3.18-3.29 (3H, m), 3.363.47 ( 1H, m), 3.77 (3H, s), 5.67 (1H, dd), 6.16 (1H, dd), 6.48 (1H, dd), 6.54 (1H, s), 7.12 (1H, t), 7.37 (1H , t), 7.43 (1H, s), 8.28-8.46 (2H, m), 8.55 (1H, s), 8.83 (1H, d), 8.94 (1H, s), 9.37 (1H, s); m/z: ES ⁺ MH ⁺ 533.5.

Example 5 methoxyphenyl}prop-2-enamide.

A solution of acryloyl chloride (0.038 ml, 0.47 mmol) in CH ₂ Cl ₂ (1 ml) was added dropwise to a stirred solution of Io(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2- yl)-4-(3-dimethylaminoazetidin-1-yl)-6-methoxybenzene-1,3-diamine (Intermediate 24, 220 mg, 0.47 mmol) and DIPEA (0.090 ml, 0.52 mmol) in CH2Cl2 (5 ml), which was cooled in an ice/water bath. The mixture was stirred for 3 hours and then washed with brine, dried (Na2SO4) and concentrated in vacuo. As a result of purification by FCC, eluting with 0-5% 7N. methanolic ammonia in CH2Cl2 gave the title compound (221 mg, 90%) as a yellow solid.

1H NMR: 2.09 (6H, s), 3.08 (1H, p), 3.55-3.62 (2H, m), 3.76 (3H, s), 3.97 (2H, t), 5.66 (1H, dd), 6.16 (1H , dd), 6.25 (1H, s), 6.45 (1H, dd), 7.10 (1H, dd), 7.35 (1H, s), 7.39 (1H, dd), 8.25-8.40 (1H, m), 8.35 ( 1H, s), 8.45 (1H, s), 8.81 (1H, d), 8.92 (1H, s), 9.24 (1H, s); m/z: ES+MH+ 519.56.

Example 6 prop-2-enamide.

Acryloyl chloride (1.248 ml, 1 M in THF, 1.25 mmol) was added dropwise k Y-[5-chloro-4(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]-N ^1- [2-(dimethylamino)ethyl]-5-methoxy- ^N1- methylbenzene1,2,4-triamine (Intermediate 33, 530 mg, 1.13 mmol) and DIPEA (0.244 ml, 1.36 mmol) in THF (20 ml), which was cooled to 0°C. This mixture was stirred at 0°C for 2 hours. The mixture was then concentrated in vacuo. The resulting residue was dissolved in CH2Cl2 (100 ml), then washed successively with saturated NaHCO ₃ (25 ml), water (25 ml) and saturated brine (25 ml). The organic solution was concentrated in vacuo. Purification by FCC eluting with 0-20% 2 M methanol ammonia in CH ₂ Cl ₂ and further purification by FCC eluting with 0-20% CH ₃ OH in

- 26 046985

CH2C12, a brown resin was obtained. LC-MS analysis showed that impurities were still present. Additional purification was undertaken by FCC, eluting with 0-20% CH3OH in CH ₂ Cl ₂ . The appropriate fractions were concentrated to obtain a brown gum containing the title compound. Attempts to turn this resin into a solid by grinding have failed. Lyophilization from CH ₃ CN/water also failed, but lyophilization from CH ₃ OH/water gave a brown semi-solid. Trituration of the semi-solid with diethyl ether followed by evaporation of the ether gave the title compound (191 mg, 32%) as a pale yellow powdery solid.

^1H NMR (CDCl3): 2.28 (6H, s), 2.32 (2H, t), 2.71 (3H, s), 2.84-2.92 (2H, m), 3.87 (3H, s), 5.67 (1H, dd) , 6.29 (1H, dd), 6.37 (1H, dd), 6.80 (1H, s), 6.89 (1H, td), 7.23-7.33 (1H, m), 7.46 (1H, s), 8.45 (1H, s ), 8.52 (1H, d), 8.56 (1H, d), 8.94 (1H, s), 9.39 (1H, s), 10.09 (1H, s); m/z: ES ⁺ MH ⁺ 521.29.

Example 7. N-{2-[(3aR,6aR)-5-Methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,2-c]pyrrol-1-yl]-5-[( 5-chloro4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-4-methoxyphenyl}prop-2-enamide.

Acryloyl chloride (1 M in THF, 0.225 ml, 0.22 mmol) in CH ₂ Cl ₂ (1 ml) was added dropwise to the mixture of 4[(3aR,6aR)-5-methyl-2,3,3a,4,6 ,6a-hexahydropyrrolo[3,2-c]nurrol-1-yl]-N-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-6-methoxybenzene- 1,3-diamine (Intermediate 35, 105 mg, 0.21 mmol) and DIPEA (0.041 ml, 0.24 mmol) in CH ₂ Cl ₂ (3 ml), which was cooled in an ice/water bath. The mixture was stirred for 0.5 h, washed with brine and then concentrated in vacuo. As a result of purification by FCC, eluting with 0-2.5% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (60 mg, 52%) as a pale yellow solid.

^1H NMR: 1.77-1.81 (1H, m), 1.95-2.16 (5H, m), 2.24-2.35 (1H, m), 2.38-2.48 (1H, m), 2.86-2.90 (1H, m), 3.18 -3.22 (1H, m), 3.37-3.45 (1H, m), 3.76 (3H, s), 4.33-4.37 (1H, m), 5.68 (1H, dd), 6.18 (1H, dd), 6.51 (1H , dd), 6.66 (1H, s), 7.10 (1H, dt), 7.33-7.41 (1H, m), 7.65 (1H, s), 8.3-8.4 (2H, m), 8.56 (1H, s), 8.81 (1H, d), 8.94 (1H, s), 9.38 (1H, s); m/z: ES ⁺ , MH ⁺ 545.57.

Example 8 [3.4]octan-2-yl]phenyl}prop-2-enamide.

A solution of acryloyl chloride (5.71 mg, 0.06 mmol) in CH ₂ Cl ₂ (1 ml) was added dropwise to a mixture of N'-(5chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2 -yl)-4-methoxy-6-(5-methyl-2,5-diazaspiro[3.4]octan-2yl)benzene-1,3-diamine (Intermediate 45, 31 mg, 0.06 mmol) in CH ₂ Cl ₂ (5 ml), which was cooled in an ice/water bath. The mixture was stirred for 3 hours and then washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. As a result of purification by FCC, eluting with 0-2% 7N. methanolic ammonia in CH2Cl2 gave the title compound (21 mg, 61%) as a yellow foam.

^1H NMR: 1.70 (2H, dd), 1.98-2.11 (2H, m), 2.37 (3H, s), 2.62 (2H, t), 3.65 (2H, d), 3.76 (3H, s), 3.95 ( 2H, d), 5.67 (1H, d), 6.09-6.27 (2H, m), 6.43 (1H, dd), 7.10 (1H, t), 7.30 (1H, s), 7.34-7.45 (1H, m) , 8.35 (2H, s), 8.44 (1H, s), 8.81 (1H, d), 8.92 (1H, s), 9.20 (1H, s); m/z: ES ⁺ MH ⁺ 545.5.

Example 9 -2H-pyridin-4-yl]phenyl}nrop-2-enamide.

A solution of acryloyl chloride (0.026 ml, 0.32 mmol) in CH ₂ Cl ₂ (1 ml) was added dropwise to the mixture of N'-(5chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl )-4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4yl)benzene-1,3-diamine (Intermediate 55, 150 mg, 0.32 mmol) and DIPEA (0.062 ml , 0.36 mmol) in CH ₂ Cl ₂ (5 ml), which was cooled in an ice/water bath. The mixture was stirred for 3 hours and then washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. As a result of purification by FCC, eluting with 2.5% 7N. methanolic ammonia in CH2Cl2 gave the title compound (120 mg, 72%) as a yellow foam.

^1H NMR: 2.28 (3H, s), 2.38 (2H, s), 2.54 (2H, t), 2.98 (2H, d), 3.81 (3H, s), 5.62-5.73 (2H, m), 6.14 ( 1H, dd), 6.43 (1H, dd), 6.88 (1H, s), 7.12 (1H, dt), 7.39-7.47 (1H, m), 7.83 (1H, s), 8.41-8.50 (2H, m) , 8.63 (1H, s), 8.85 (1H, d), 8.95 (1H, s), 9.36 (1H, s); m/z: ES+MH+ 516.25.

Example 10. No. {5-[(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-2-[4-(2dimethylamino-2-oxoethyl)piperazin- 1-yl]-4-methoxyphenyl}-prop-2-enamide.

A solution of acryloyl chloride (0.030 ml, 0.37 mmol) in CH ₂ Cl ₂ (1 ml) was added dropwise to a stirred solution of 2-(4-{2-amino-4-[(5-chloro-4-pyrazolo[1, 5-a]pyridin-3-ylpyrimidin-2-yl)amino]-5methoxyphenyl}piperazin-1-yl)-IX-dimethylacetamide (Intermediate 57, 0.19 g, 0.35 mmol) and DIPEA (0.067 ml, 0.39 mmol) in CH ₂ Cl ₂ (5 ml). The mixture was stirred for 0.5 h, then diluted with CH ₂ Cl ₂ (20 ml) and washed with saturated brine (2x25 ml). The organic solution was dried (MgSO4) and concentrated in vacuo. Purification by FCC eluting with 5% CH3OH in CH2Cl2 gave the title compound (0.157 g, 75%) as a yellow solid.

^1H NMR (CDCl3): 2.76 (4H, s), 2.90-2.96 (4H, m), 2.98 (3H, s), 3.12 (3H, s), 3.30 (2H, s), 3.87 (3H, s) , 5.65-5.77 (1H, m), 6.18-6.37 (2H, m), 6.80 (1H, s), 6.90 (1H, t), 7.28 (1H, d), 7.42 (1H, s), 8.44 (1H , s), 8.468.59 (3H, m), 8.93 (1H, s), 9.33 (1H, s); m/z: ES+MH+ 590.52.

Example 11. ^)-N-{2-[4-(2-Aminopropanoyl)piperazin-1-yl]-5-[(5-chloro-4-pyrazolo[1,5-a]pyridin-27 046985

-ylpyrimidin-2-yl)amino]-4-methoxyphenyl}prop-2-enamide.

A solution of acryloyl chloride (10.2 µl, 0.13 mmol) in CH ₂ Cl ₂ (3 ml) was added dropwise to the stirred solution of (b)-tert-butyl-H-[1-(4-{2-amino-4 -[(5-chloro-4-pyrazolo[1.5-a|pyridin-3-ylpyrimidin2-yl)amino]-5-methoxyphenyl}piperazin-1-yl)-1-oxopropan-2-yl]carbamate (Intermediate 59 , 65 mg) and DIPEA (0.75 ml) in CH ₂ Cl ₂ (10 ml), which was cooled in an ice/water bath. The mixture was stirred for 0.75 h, then quenched with water (10 ml) and 2M Na ₂ CO ₃ (5 ml). The phases were separated and the organic solution was dried (MgSO ₄ ) and concentrated in vacuo. The resulting residue was dissolved in CH ₂ Cl ₂ (3 ml) and then treated with TFA (0.1 ml). After standing for 0.25 h, a second portion of TFA (0.2 ml) was added. After another 0.25 hour period, this solution was concentrated in vacuo and purified by preparative HPLC (Waters SunFire column, 5 µm silica, 19 mm diameter, 100 mm length), eluting with mixtures of decreasing polarity water (containing 0.1% formic acid) and CH3CN. Fractions containing the title compound were concentrated in vacuo to give the title compound (17 mg, 6% of 5-chloro-N(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5a|pyridine -3-yl-pyrimidin-2-amine) as a white solid.

Ή NMR: 1.25 (3H, s), 2.83-2.96 (4H, m), 3.65-3.82 (7H, m), 4.14-4.23 (1H, m), 5.73 (1H, d), 61.9 (1H, d) , 6.64-6.70 (1H, m), 6.69 (1H, s), 7.08-7.12 (1H, m) 7.30-7.37 (1H, m), 8.20-8.28 (2H, m), 8.35-8.41 (2H, m ), 8.68 (1H, s), 8.80-8.84 (1H, m), 8.95 (1H, s), 9.11-9.15 (1H, m); m/z: ES ⁺ MH ⁺ 576.60.

Example 12 -4-methoxyphenyl}prop-2-enamide.

A solution of acryloyl chloride (0.042 ml, 0.52 mmol) in CH ₂ Cl ₂ (1 ml) was added dropwise to the mixture of N)-Ni-[5-chloro-4-(pyrazolo[1,5-a]pyridin-3- yl)pyrimidin-2-yl]-4-[3-(dimethylamino)pyrrolidin-1-yl]6-methoxybenzene-1,3-diamine (Intermediate 61, 250 mg, 0.52 mmol) and DIPEA (0.099 ml , 0.57 mmol) in CH2Cl2 (5 ml), which was cooled in an ice/water bath. The mixture was stirred for 3 hours and then washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. As a result of purification by FCC, eluting with 2% 7N. methanolic ammonia in CH2Cl2 gave the title compound (194 mg, 70%) as a yellow solid.

Ή NMR: 1.69-1.83 (1H, m), 2.05-2.16 (1H, m), 2.19 (6H, s), 2.65-2.78 (1H, m), 3.18-3.29 (3H, m), 3.353.46 ( 1H, m), 3.77 (3H, s), 5.67 (1H, dd), 6.16 (1H, dd), 6.48 (1H, dd), 6.54 (1H, s), 7.12 (1H, t), 7.37 (1H , t), 7.43 (1H, s), 8.3-8.46 (2H, m), 8.55 (1H, s), 8.83 (1H, d), 8.94 (1H, s), 9.37 (1H, s); m/z: ES ⁺ MH ⁺ 533.5.

Example 13. No. {5-[(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-4-methoxy-2-[4methylpiperazin-1 -yl]phenyl }prop-2-enamide.

A solution of acryloyl chloride (0.092 ml, 1.14 mmol) in CH2C12 (1 ml) was added dropwise to a mixture of N(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4 -methoxy-6-(4-methylpiperazin-1-yl)benzene1,3-diamine (Intermediate 63, 480 mg, 1.03 mmol) and DIPEA (0.214 ml, 1.24 mmol) in CH ₂ Cl ₂ (18 ml) at room temperature After 0.25 h, additional acryloyl chloride (15 mg in 0.15 ml CH2Cl2) was added. The mixture was stirred for 0.5 h and then washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2.5% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (390 mg, 73%) as a yellow solid after trituration with CH ₃ OH.

^1H NMR: 2.27 (3H, s), 2.53-2.61 (4H, m), 2.84-2.97 (4H, m), 3.77 (3H, s), 5.70 (1H, d), 6.17 (1H, d), 6.61 (1H, dd), 6.89 (1H, s), 7.11 (1H, t), 7.3-7.42 (1H, m), 8.10 (1H, s), 8.26-8.47 (2H, m), 8.70 (1H, s), 8.83 (1H, d), 8.96 (1H, s), 9.02 (1H, s); m/z: ES ⁺ MH ⁺ 519.

Example 14. N{5-[(5-Cyano-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-4-methoxy-2-[4methylpiperazin-1 -yl]phenyl }prop-2-enamide.

A solution of acryloyl chloride (0.017 ml, 0.21 mmol) in CH ₂ Cl ₂ (0.6 ml) was added to the mixture of 2-{[5-amino-2methoxy-4-(4-methylpiperazin-1-yl)phenyl] amino } -4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-5 carbonitrile (Intermediate 65, 87 mg, 0.19 mmol) and DIPEA (0.063 ml, 0.38 mmol) in CH ₂ Cl ₂ (1 .5 ml) at 0°C. The mixture was then stirred at 0°C for 4 hours (during which time an additional 0.5 eq of acryloyl chloride was added). The mixture was then diluted with CH ₂ Cl ₂ , washed twice with saturated NaHCO ₃ , then with water and then dried (MgSO ₄ ). Purification by FCC eluting with 0-6% methanol ammonia in CH ₂ Cl ₂ gave the title compound (67 mg, 69%) as a yellow solid.

Ή NMR: (102°С) 2.30 (3H, s), 2.56-2.59 (4H, m), 2.93-2.96 (4H, m), 3.78 (3H, s), 5.67-5.7 (1H, m), 6.16 (1H, d), 6.44-6.51 (1H, m), 6.95 (1H, s), 7.11 (1H, t), 7.35 (1H, t), 8.20 (1H, s), 8.32 (1H, d), 8.66 (1H, s), 8.72 (1H, br s), 8.76 (1H, d), 8.91 (1H, s), 8.96 (1H, br s); m/z: ES+MH+ 510.5.

Example 15 enamide

To a stirred solution of N-[4-(1H-indol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine (Intermediate 66 , 96 mg, 0.22 mmol) in CH2Cl2 (15 ml) at 2°C was added DIPEA (0.039 ml, 0.22 mmol) and acryloyl chloride (0.018 ml, 0.22 mmol). The resulting solution was stirred at 2°C for 0.25 h, then left to warm to room temperature. and stirred for another 3.5 hours. The mixture was then diluted with CH3OH (10 ml), loaded directly onto the dioxide cream

- 28 046985 nia. Purification by FCC eluting with 0-10% CH3OH in CH2C12 (containing 1% concentrated ammonia (aq)) yielded an off-white solid that appeared to contain DIPEA-HCl by NMR analysis. This solid was then dissolved in 1:1 CH ₂ Cl ₂ /2-methyltetrahydrofuran (30 ml) and the resulting solution was washed with NaOH solution (2 M, 2x30 ml), water (2x30 ml) and then saturated brine (30 ml). The organic solution was dried (MgSO ₄ ) and concentrated in vacuo to give the title compound (2 mg, 2%) as a white solid after trituration with diethyl ether. The trituration mother liquors were concentrated in vacuo to obtain a second sample of the title compound (10 mg, 9%) as a white solid.

^1H NMR: 2.27 (3H, s), 2.55 (4H, s), 2.82-2.95 (4H, m), 3.84 (3H, d), 5.73 (1H, d), 6.24 (1H, dd), 6.62 ( 1H, dd), 6.89 (1H, s), 7.07-7.21 (2H, m), 7.25 (1H, d), 7.46 (1H, d), 7.89 (1H, s), 8.29 (1H, d), 8.32 (1H, d), 8.42 (1H, s), 8.69 (1H, s), 9.01 (1H, s); m/z: ES ⁺ MH ⁺ 484.62.

Example 16 -2-enamid.

(2,3,4,5,6-Pentafluorophenyl)prop-2-enoate (0.030 ml, 0.19 mmol) was added dropwise to a solution of 4methoxy-6-(4-methylpiperazin-1-yl)-N'-( 4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3diamine (Intermediate 69, 67 mg, 0.16 mmol) in DMF (0.6 ml) at RT . in an N2 atmosphere. The resulting solution was stirred at room temperature. for 1.5 h and then diluted with CH ₂ Cl ₂ (9 ml). This solution was added to flash chromatography silica l.5g, which was wetted with CH ₂ Cl ₂ in a dry-loaded cartridge, and the crude product was eluted from the silica using CH ₂ Cl ₂ . As a result of additional purification by FCC, eluting with 2-7% 2N. methanol ammonia in CH ₂ Cl ₂ produced material that was further purified by FCC, eluting with 5-20% CH ₃ OH in CH ₂ Cl ₂ . The appropriate fractions were concentrated in vacuo and trituration gave a crystalline solid which was washed with THF (0.1 mL) to give the title compound (23 mg, 28%) as a beige crystalline solid.

^1H NMR: 2.33-2.43 (3H, m), 2.62-2.81 (4H, m), 2.94 (4H, s), 3.85 (3H, s), 5.72 (1H, d), 6.18 (1H, m), 6.55-6.69 (1H, m), 6.89 (1H, s), 7.05 (1H, m), 7.26 (1H, d), 7.35-7.43 (1H, m), 8.15 (1H, s), 8.34 (1H, d), 8.44 (1H, d), 8.49 (1H, s), 8.79 (1H, d), 8.80 (1H, s), 9.03 (1H, s); m/z: ES ⁺ MH ⁺ 485.

Example 17 )prop-2-enamide.

Acryloyl chloride (0.621 ml, 1 M in THF, 0.62 mmol) was added dropwise to Na-[5-chloro-4-(III-indol3-yl)pyrimidin-2-yl]-4-methoxy-6-(4 -methylpiperazin-1-yl)benzene-1,3-diamine (Intermediate 74, 288 mg, 0.62 mmol) and DIPEA (0.119 ml, 0.68 mmol) in THF (15 ml) at 0°C atmosphere N2. The resulting suspension was stirred at 0°C for 1 hour and then left to warm to room temperature. The mixture was then diluted with water (15 ml) and concentrated in vacuo. The resulting residue was dissolved in a mixture of CH2Cl2 (20 ml) and CH3OH (5 ml) and the resulting solution was washed with water and saturated brine. The organic solution was dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC, eluting with 1-8% 7M methanolic ammonia in CH2Cl2, gave the crude product as a pale brown dry film. This material was dissolved in CH2Cl2 and a beige solid precipitated from solution. This solution was diluted with diethyl ether and then the mixture was filtered. The collected solid was washed with additional diethyl ether and dried to give the title compound (134 mg, 42%) as a beige solid.

1H NMR: 2.27 (3H, s), 2.53-2.59 (4H, m), 2.87-2.94 (4H, m), 3.79 (3H, s), 5.70 (1H, d), 6.17 (1H, dd), 6.60 (1H, dd), 6.89 (1H, s), 7.01 (1H, t), 7.16 (1H, t), 7.45 (1H, d), 8.20 (1H, s), 8.27 (1H, d), 8.35 ( 1H, s), 8.43 (1H, s), 8.49 (1H, d), 8.96 (1H, s), 11.81 (1H, s); m/z: ES+MH+ 518.51.

Example 18. No(4-Methoxy-5-{[5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}-2-{4methylpiperazin-1-yl}phenyl)prop- 2-enamid.

Acryloyl chloride (0.358 ml, 1 M in THF, 0.36 mmol) was added dropwise to a mixture of 4-methoxy-N'-[5methyl-4-(1-methylindol-3-yl)pyrimidin-2-yl]-6- (4-methylpiperazin-1-yl)benzene-1,3-diamine (Intermediate 77, 164 mg, 0.36 mmol) and DIPEA (0.069 ml, 0.39 mmol) in THF (15 ml) at 0°C in an N2 atmosphere. The resulting suspension was stirred at 0°C for 1 hour, then left to warm to room temperature. The mixture was then diluted with water (15 ml) and concentrated in vacuo. The resulting material was dissolved in a mixture of CH ₂ Cl ₂ (20 ml) and CH ₃ OH (5 ml). The resulting solution was washed with water and saturated brine. The organic solution was then dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC, eluting with 1-8% 7 M methanol ammonia in CH ₂ Cl ₂ , after concentrating the appropriate fractions in vacuo, gave a yellow dry film. This material was dissolved in CH ₂ Cl ₂ and the resulting solution was diluted with diethyl ether, resulting in a beige solid precipitating out of solution. This solid was collected by filtration, washed with diethyl ether and then dried to give the title compound (96 mg, 52%).

1H NMR: 2.26 (3H, s), 2.37 (3H, s), 2.51 (4H, s), 2.87 (4H, s), 3.83 (3H, s), 3.89 (3H, s), 5.70 (1H, d ), 6.17 (1H, d), 6.60 (1H, dd), 6.86 (1H, s), 7.09 (1H, t), 7.22 (1H, t), 7.48 (1H, d), 7.87 (1H, s) , 8.05 (1H, s), 8.21 (1H,

- 29 046985

s), 8.37 (1H, d), 8.46 (1H, s), 9.00 (1H, s); m/z: ES ⁺ MH ⁺ 512.46.

Example 19. H-(2-{2-Dimethylaminoethyl-methylamino}-4-methoxy-5-{[5-methyl-4-(1-methylindol-3yl)pyrimidin-2-yl]amino}phenyl)prop-2 -enamid.

Acryloyl chloride (0.026 ml, 1 M in THF, 0.32 mmol) was added dropwise to a mixture of N ¹ -(2-dimethylaminoethyl)-5-methoxy-N-methyl-H ⁴ -[5-methyl-4-(1- methylindol-3-yl)pyrimidin-2yl]benzene-1,2,4-triamine (Intermediate 81, 147 mg, 0.32 mmol) and DIPEA (0.061 ml, 0.35 mmol) in THF (15 ml) at 0°C in N ₂ atmosphere. The resulting suspension was stirred at 0°C for 1 hour, then left to warm to room temperature. The mixture was then diluted with water (15 ml) and concentrated in vacuo. The resulting material was dissolved in a mixture of CH ₂ Cl ₂ (20 ml) and CH ₃ OH (5 ml). The resulting solution was washed with water and saturated brine and then dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC, eluting with 1-8% 7 M methanol ammonia in CH ₂ Cl ₂ , after concentrating the appropriate fractions in vacuo, gave a yellow dry film. This material was dissolved in CH2Cl2 and the resulting solution was diluted with diethyl ether. This solution was concentrated in vacuo and dried to give the title compound (93 mg, 57%) as a beige solid.

1H NMR: 2.21 (6H, s), 2.28-2.34 (2H, m), 2.37 (3H, s), 2.73 (3H, s), 2.89 (2H, t), 3.81 (3H, s), 3.89 (3H , s), 5.72 (1H, dd), 6.19 (1H, dd), 6.38 (1H, dd), 7.02 (1H, d), 7.06 (1H, d), 7.18-7.23 (1H, m), 7.48 ( 1H, d), 7.91 (1H, s), 8.06 (1H, s), 8.22 (1H, s), 8.36 (1H, d), 8.75 (1H, s), 10.11 (1H, s); m/z: ES'MH' 514.36.

Example 20 } phenyl)prop-2-enamide.

Acryloyl chloride (0.043 mL, 1 M in THF, 0.53 mmol) was added dropwise to a mixture of 4-[(3R)-3dimethylaminopyrrolidin-1-yl]-6-methoxy-H-[5-methyl-4-(1- methylindol-3-yl)-pyrimidin-2-yl]benzene1,3-diamine (Intermediate 83, 252 mg, 0.53 mmol) and DIPEA (0.103 ml, 0.59 mmol) in THF (15 ml) at 0 °C in N2 atmosphere. The resulting suspension was stirred at 0°C for 1 hour and then left to warm to room temperature. The mixture was then diluted with water (15 ml) and concentrated in vacuo. The resulting material was dissolved in a mixture of CH ₂ Cl ₂ (20 ml) and CH ₃ OH (5 ml). The resulting solution was washed with water and saturated brine. The aqueous washes were again extracted three times using CH ₂ Cl ₂ . The combined organic solutions were dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC, eluting with 1-8% CH ₃ OH in CH ₂ Cl ₂ , yielded a yellow dry film after concentrating the appropriate fractions in vacuo. This material was dissolved in CH ₂ Cl ₂ and the resulting solution was diluted with diethyl ether. The resulting mixture was stirred for 30 minutes and then concentrated in vacuo to give the title compound (133 mg, 47%) as a yellow solid.

1H NMR: 1.67-1.81 (1H, m), 2.09 (1H, s), 2.19 (6H, s), 2.35 (3H, s), 2.72 (1H, s), 3.20 (3H, t), 3.30-3.43 (1H, m), 3.84 (3H, s), 3.89 (3H, s), 5.66 (1H, d), 6.16 (1H, d), 6.49 (1H, dd), 6.55 (1H, s), 7.12 ( 1H, t), 7.22 (1H, t), 7.48 (1H, d), 7.75 (1H, s), 7.92 (1H, s), 8.02 (1H, s), 8.18 (1H, s), 8.40 (1H , d), 9.32 (1H, s); m/z: ES+MH+ 526.66.

Example 21. N-(5-{[5-Chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}-2-{(3R)-3-dimethylaminopyrrolidin-1-yl}- 4-methoxyphenyl)prop-2-enamide.

Acryloyl chloride (0.459 ml, 1M in THF, 0.46 mmol) at 0°C under N2 was added dropwise to the mixture of H-[5-chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl] - 4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6methoxybenzene-1,3-diamine (Intermediate 85, 226 mg, 0.46 mmol) and DIPEA (0.088 ml, 0.51 mmol) in THF ( 15 ml). The resulting suspension was stirred at 0°C for 1 hour, then left to warm to room temperature. The mixture was then diluted with water (15 ml) and concentrated in vacuo. The resulting material was dissolved in a mixture of CH2Cl2 (20 ml) and CH3OH (5 ml). The resulting solution was washed with water and sat. brine. The organic solution was dried (MgSO4) and concentrated in vacuo. Purification by FCC eluting with 1-8% 7M methanol ammonia in CH2Cl2 and concentrating the appropriate fractions in vacuo gave a yellow dry film. This material was dissolved in CH ₂ Cl ₂ and the resulting solution was diluted with diethyl ether. The result was a yellow, gelatinous solid that precipitated out of solution. The mixture was concentrated in vacuo and dried to give the title compound (142 mg, 57%) as a yellow solid.

1H NMR: 1.68-1.81 (1H, m), 2.04-2.14 (1H, m), 2.18 (6H, s), 2.64-2.75 (1H, m), 3.22 (3H, dd), 3.32-3.44 (1H, m), 3.78 (3H, s), 3.90 (3H, s), 5.66 (1H, dd), 6.16 (1H, dd), 6.49 (1H, dd), 6.54 (1H, s), 7.08 (1H, t ), 7.23 (1H, t), 7.49 (1H, d), 7.54 (1H, s), 8.29-8.39 (3H, m), 8.53 (1H, s), 9.35 (1H, s); m/z: ES ⁺ MH ⁺ 546.57.

Example 22. N-(5-{[5-Cyano-4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}-2-{(3R)-3-dimethylaminopyrrolidin-1-yl}- 4-methoxyphenyl)prop-2-enamide.

Acryloyl chloride (0.373 ml, 1M in THF, 0.37 mmol) at 0°C under N2 was added dropwise to a mixture of 2({5-amino-4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2- methoxyphenyl}amino)-4-(1-methylindol-3yl)pyrimidin-5-carbonitrile (Intermediate 89, 180 mg, 0.37 mmol) and DIPEA (0.072 mL, 0.41 mmol) in THF (15 mL) . The resulting suspension was stirred at 0°C for 1 hour, then left to warm to room temperature. The mixture was diluted with water (15 ml) and then concentrated in vacuo. Received

- 30 046985 the material was dissolved in a mixture of CH2C12 (20 ml) and CH3OH (5 ml). The resulting solution was washed with water and sat. brine. The organic solution was dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 1-8% 7 M methanolic ammonia in CH ₂ Cl ₂ and concentrating the appropriate fractions in vacuo gave a yellow dry film. This material was dissolved in CH ₂ Cl ₂ and the resulting solution was diluted with diethyl ether. A yellow gelatinous solid then precipitated out of solution. Concentrating the mixture in vacuo gave the title compound (91 mg, 46%) as a yellow solid.

1H NMR (100°C): 1.82 (1H, dq), 2.04-2.11 (1H, m), 2.22 (6H, d), 2.85 (1H, dd), 3.20-3.39 (4H, m), 3.79 (3H , s), 3.90 (3H, s), 5.62 (1H, d), 6.16 (1H, dd), 6.45 (1H, dd), 6.62 (1H, s), 7.10 (1H, t), 7.25 (1H, t), 7.49 (1H, d), 7.65 (1H, s), 8.26 (1H, d), 8.42 (1H, s), 8.59 (1H, s), 8.72 (1H, s), 8.93 (1H, s ); m/z: ES+MH+ 537.61.

Example 23 2-enamid.

A solution of acryloyl chloride (39 mg, 0.43 mmol) in CH ₂ Cl ₂ (1 ml) was added dropwise to the stirred solution of 2-{[5-amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl ]amino}-4-(1-methylindol-3yl)pyrimidin-5-carbonitrile (Intermediate 90, 200 mg, 0.43 mmol) and DIPEA (0.081 ml, 0.47 mmol) in CH ₂ Cl ₂ (5 ml ), which was cooled in an ice/water bath. The mixture was stirred for 1.5 hours and then diluted with CH ₂ Cl ₂ (25 ml). This mixture was then washed with sat. NaHCO ₃ (50 ml). The aqueous washes were further extracted with CH ₂ Cl ₂ (2x25 ml). The combined organic solutions were dried (MgSO ₄ ) and concentrated in vacuo. As a result of purification by FCC eluting with 5% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound along with some residual starting material. Purification by FCC eluting with 0-5% CH3OH in CH2Cl2 and concentrating the appropriate fractions in vacuo gave a residue. This residue was dissolved in a small amount of CH2Cl2 and trituration with diethyl ether gave a solid which was collected by filtration and dried in vacuo to give the title compound (106 mg, 48%) as a cream solid.

1H NMR: 2.27 (3H, s), 2.57 (4H, br s), 2.92 (4H, br s), 3.74 (3H, s), 3.91 (3H, s), 5.70 (1H, d), 6.17 (1H , d), 6.63 (1H, dd), 6.90 (1H, s), 7.01 (1H, br s), 7.25 (1H, s), 7.52 (1H, d), 7.88 (1H, br s), 8.02 ( 1H, s), 8.48 (1H, s), 8.67 (1H, s), 9.03 (1H, s), 9.40 (1H, s); m/z: ES ⁺ MH ⁺ 523.27.

Example 24. N-(5-{[5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-2-{(3R)-3-dimethylaminopyrrolidin-1-yl}- 4-methoxyphenyl)prop-2-enamide.

A solution of acryloyl chloride (0.044 ml, 0.54 mmol) in CH ₂ Cl ₂ (1 ml) was added dropwise to the mixture of N-[5chlor-4-(N-indol-3-yl)pyrimidin-2-yl]-4- [(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxybenzene1,3-diamine (Intermediate 93, 258 mg, 0.54 mmol) and DIPEA (0.103 mL, 0.59 mmol) in CH2Cl2 (5 mL ), which was cooled in an ice/water bath. The mixture was stirred for 3 hours and then washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The resulting residue was suspended in CH3OH and filtered to obtain some amount of the title compound (67 mg). The filtrate was then concentrated in vacuo and purified by FCC, eluting with 2% 7N. methanol ammonia in CH2Cl2. The appropriate fractions were combined and concentrated in vacuo to give a solid, which was suspended in CH ₃ OH and collected by filtration to give additional amount of the title compound (64 mg). Two batches of product were combined to give the title compound (131 mg, 46%) as a yellow solid.

1H NMR: 1.68-1.83 (1H, m), 2.04-2.16 (1H, m), 2.18 (6H, s), 2.63-2.77 (1H, m), 3.15-3.29 (3H, m), 3.353.46 ( 1H, m), 3.78 (3H, s), 5.66 (1H, dd), 6.16 (1H, dd), 6.49 (1H, dd), 6.54 (1H, s), 7.04 (1H, t), 7.16 (1H , t), 7.45 (1H, d), 7.53 (1H, s), 8.23-8.4 (3H, m), 8.48 (1H, d), 9.34 (1H, s), 11.84 (1H, s); m/z: ES+MH+ 532.5.

Example 25 .

A solution of acryloyl chloride (0.027 ml, 0.33 mmol) in CH2Cl2 (1 ml) was added dropwise to a mixture of N ⁴ [5-chloro-4-(III-indol-3-yl)pyrimidin-2-yl]-H ¹ - (2-dimethylaminoethyl)-5-methoxy-H ¹ -methylbenzene-1,2,4triamine (intermediate 95, 155 mg, 0.33 mmol) and DIPEA (0.063 ml, 0.37 mmol) in CH ₂ Cl ₂ ( 5 ml), which was cooled in an ice/water bath. The mixture was stirred for 1 hour and then washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. As a result of purification by FCC eluting with 2% 7N. methanolic ammonia in CH ₂ Cl ₂ and trituration with diethyl ether gave the title compound (120 mg, 69%) as a white solid.

1H NMR: 2.22 (6H, s), 2.34 (2H, br t), 2.75 (3H, s), 2.91 (2H, brt), 3.76 (3H, s), 5.73 (1H, dd), 6.19 (1H, dd), 6.39 (1H, dd), 6.96 (1H, t), 7.05 (1H, s), 7.14 (1H, t), 7.44 (1H, d), 8.26 (1H, d), 8.35 (1H, s ), 8.48 (1H, s), 8.50 (1H, d), 8.54 (1H, s), 10.10 (1H, s), 11.85 (1H, s); m/z: ES+MH+ 520.6.

Example 26 enamide

A solution of acryloyl chloride (0.026 ml, 0.32 mmol) in CH ₂ Cl ₂ (1 ml) at 0°C was added to the mixture of ^-[5-chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl ]-NG(2-dimethylamino-ethyl)-5-methoxy-H1-methyl

- 31 046985 benzene-1,2,4-triamine (Intermediate 97, 130 mg, 0.27 mmol) and DIPEA (0.090 ml, 0.54 mmol) in CH ₂ Cl ₂ (2 ml). The mixture was stirred at 0°C for 2.5 hours (during which time an additional 0.2 eq of acryloyl chloride was added). The mixture was then diluted with CH ₂ Cl ₂ , washed twice with sat. NaHCO ₃ and then water, dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 0-5% methanol ammonia in CH ₂ Cl ₂ gave the title compound (111 mg, 77%) as a yellow solid.

1H NMR (CDCl3): 2.26 (6H, s), 2.23-2.33 (2H, m), 2.70 (3H, s), 2.86-2.89 (2H, m), 3.88 (3H, s), 3.91 (3H, s ), 5.67 (1H, d), 6.25-6.44 (2H, m), 6.79 (1H, s), 7.20-7.37 (3H, m), 7.57 (1H, s), 8.36-8.45 (3H, m), 9.54 (1H, s), 10.11 (1H, s); m/z: ES ⁺ MH ⁺ 534, 536.

Example 27 )prop-2-enamide.

Acryloyl chloride (0.100 ml, 1M in THF, 0.1 mmol) at -10°C over a period of 2 min under N2 was added dropwise to a thin suspension of 2-{[5-amino-2-methoxy-4-(4- methylpiperazin-1yl)phenyl]amino}-4-(1H-indol-3-yl)pyrimidin-5-carbonitrile (Intermediate 99, 47 mg, 0.10 mmol) and DIPEA (0.027 ml, 0.16 mmol) in THF (2 ml). The mixture was then stirred at 0°C for 10 min and then allowed to warm to room temperature. within 20 min. The mixture was then cooled again to -10°C and additional acryloyl chloride (0.06 mL, 1 M in THF, 0.06 mmol) was added dropwise. The mixture was stirred at 0°C for an additional 10 minutes, then allowed to warm to room temperature. within 20 min. The mixture was then concentrated in vacuo and the resulting residue was dissolved in CH ₂ Cl ₂ (2 ml). This solution was washed with sat. NaHCO ₃ (1 ml), dried (MgSO ₄ ) and concentrated in vacuo. As a result of purification by FCC eluting with 1.5-7% 7N. methanolic ammonia in CH ₂ Cl ₂ gave a residue which was washed with CH ₃ OH (0.1 ml) and air dried to give the title compound (11 mg, 20%) as a cream colored crystalline solid.

1H NMR: 2.28 (3H, s), 2.54-2.65 (4H, m), 2.93 (4H, s), 3.75 (3H, s), 5.71 (1H, d), 6.18 (1H, d), 6.64 (1H , dd), 6.91 (2H, m), 7.18 (1H, s), 7.47 (1H, d), 8.02 (1H, s), 8.52 (1H, s), 8.67 (1H, s), 9.04 (1H, s), 9.40 (1H, s), 11.99 (1H, s); m/z: ES+MH+ 509.

Example 28

A solution of acryloyl chloride (34.5 mg, 0.38 mmol) in CH ₂ Cl ₂ (1 ml) was added dropwise to the stirred mixture of ^-^-dimethylaminoethyl^-methoxy-^-methyl-I ⁴ - [4-( 1 - methylindol-3-yl)pyrimidin-2yl]benzene-1,2,4-triamine (Intermediate 100, 170 mg, 0.38 mmol) and DIPEA (0.073 ml, 0.42 mmol) in CH ₂ Cl ₂ (5 ml), which was cooled in an ice/water bath. The mixture was stirred for 1.5 h and then diluted with CH ₂ Cl ₂ (25 ml) and washed with sat. NaHCO ₃ (50 ml). The aqueous washes were extracted with CH ₂ Cl ₂ (2x25 ml). The combined organic solutions were dried (MgSO ₄ ) and concentrated in vacuo. As a result of purification by FCC eluting with 0-4% 7N. methanolic ammonia in CH ₂ Cl ₂ and trituration with diethyl ether gave the title compound (75 mg, 39%) as a cream-colored solid.

1H NMR: 2.21 (6H, s), 2.29 (2H, t), 2.72 (3H, s), 2.89 (2H, t), 3.86 (3H, s), 3.92 (3H, s), 5.77 (1H, dd ), 6.27 (1H, dd), 6.43 (1H, dd), 7.04 (1H, s), 7.15 (1H, t), 7.20-7.27 (2H, m), 7.53 (1H, d), 7.91 (1H, s), 8.24 (1H, d), 8.33 (1H, d), 8.68 (1H, s), 9.14 (1H, s), 10.22 (1H, s); m/z: ES+MH+ 500.42.

Example 28 (Alternate Synthesis 1). I-(2-{2-Dimethylaminoethyl-methylamino}-4-methoxy-5-{[4(1-methylindol-3-yl)pyrimidin-2-yl]amino} phenyl)prop-2-enamide

To a stirred solution of 3-chloro-I-[2-[2-dimethylaminoethyl(methyl)amino]-4-methoxy-5-[[4-(1methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]propanamide (Intermediate 174, 31.5 g, 58.76 mmol) in acetonitrile (310 ml) at RT. triethylamine (17.84 g, 176.28 mmol) was added. The resulting mixture was heated to 80°C for 6 hours, then cooled to room temperature. Then water (130 ml) was added and

- 32 046985 the mixture was stirred for 12 hours. The mixture was then filtered, washed with a mixture of water and acetonitrile (160 ml, 1:1) and dried at 50°C overnight to obtain the title compound (19.2 g, 94% ) as a solid form, identified as polymorphic form D.

1H NMR: 2.69 (3H, s), 2.83 (6H, d), 3.35 (4H, s), 3.84 (3H, s), 3.91 (3H, s), 5.75 (1H, d), 6.28 (1H, d ), 6.67 (1H, dd), 7.05-7.23 (2H, m), 7.29 (1H, t), 7.43 (1H, d), 7.56 (1H, d), 8.21 (2H, s), 8.81 (1H, s), 9.47 (1H, s), 9.52 (1H, s), m/z: ES+MH+ 500.26.

Example 28 (Alternate Synthesis 2). N(2-{2-Dimethylaminoethyl-methylamino}-4-methoxy-5-{[4(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

To a stirred solution of Y-(2-dimethylaminoethyl)-5-methoxy-U-methyl-U-[4-(1-methylindol3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine (Intermediate 100 , 10 g, 21.32 mmol) in THF (95 ml) and water (9.5 ml) at 0°C was added 3-chloropropanoyl chloride (3.28 g, 25.59 mmol). The mixture was stirred at room temperature. for 15 min, then NaOH (3.48 g, 85.28 mmol) was added. The resulting mixture was heated to 65°C for 10 hours. The mixture was then cooled to room temperature. and CH ₃ OH (40 ml) and water (70 ml) were added. The resulting mixture was stirred overnight. The resulting solid was collected by filtration, washed with water (25 ml) and dried at 50°C for 12 hours to obtain the title compound (7.0 g, 94%) as a solid form, identified as polymorph Form D.

1H NMR: 2.69 (3H, s), 2.83 (6H, d), 3.35 (4H, s), 3.84 (3H, s), 3.91 (3H, s), 5.75 (1H, d), 6.28 (1H, d ), 6.67 (1H, dd), 7.05-7.23 (2H, m), 7.29 (1H, t), 7.43 (1H, d), 7.56 (1H, d), 8.21 (2H, s), 8.81 (1H, s), 9.47 (1H, s), 9.52 (1H, s); ES+ MH+ 500.26.

Example 28A. ^(2-{2-Dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide, mesylate salt

Procedure 1: To a stirred solution of ^[2-[2-dimethylaminoethyl(methyl)amino]-4-methoxy-5[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop- 2-enamide (example 28, 20 g, 36.63 mmol) in ethanol (120 ml) and EtOAc (80 ml) at 70°C was added methanesulfonic acid (3.59 g, 36.63 mmol) as a solution in EtOAc (40 ml). The resulting mixture was stirred for 1.5 hours. The resulting solid was collected by filtration and dried at 80° C. under vacuum overnight to obtain the title salt (20.5 g, 94%) in solid form, identified as polymorph B for this salt.

Procedure 2: To a stirred solution of ^[2-[2-dimethylaminoethyl(methyl)amino]-4-methoxy-5[[4-(1-methylindol-3-yl)pyrimidin-2-yl]-amino]phenyl]prop -2-enamide (example 28, 5 g, 9.11 mmol) in acetone (45.5 ml) and water (4.55 ml) at 50°C was added methanesulfonic acid (0.893 g, 9.11 mmol) as solution in acetone (4.55 ml). The resulting mixture was stirred for 1.5 hours. The resulting solid was collected by filtration and dried at 80° C. under vacuum overnight to obtain the title salt (4.9 g, 94%) in solid form, identified as polymorph Form B for this salt.

1H NMR (acetone^): 2.72 (3H, s), 2.96 (3H, s), 3.01 (6H, s), 3.58 (3H, t), 3.87-3.90 (7H, m), 5.76 (1H, dd) , 6.38-6.53 (2H, m), 7.12 (1H, t), 7.20 (1H, t), 7.29 (1H, s), 7.40 (2H, t), 8.07-8.16 (3H, m), 8.56 (1H , s), 9.30 (1H, s), 9.60 (1H, s), 9.66 (1H, s); m/z: ES+ MH ⁺ 500.26.

Procedure 3: Polymorph Form A of the mesylate salt No.(2-{2-dimethylaminoethyl-methylamino}-4methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2 -enamide was prepared similarly to that described above on a scale of approximately 50 mg, except that acetonitrile was used as a solvent. More specifically, approximately 9.6 mg of methanesulfonic acid was dissolved in a minimum volume of acetonitrile. Approximately 50 mg ^{2-{2-dimethylamino-ethylmethylamino}-4-methoxy-5-{[4-( 1 -methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide also

- 33 046985 was dissolved in a minimum volume of acetonitrile and then the resulting solution was added to the methanesulfonic acid solution. Upon addition, a solid formed. This solid was collected by filtration and air dried and then analyzed. The specific solid form obtained in this experiment was designated polymorph A of this salt.

Example 29. No. (5-{[5-Cyano-4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}-2-{2-dimethylaminoethyl-methylamino}-4-methoxyphenyl)prop-2 -enamid.

A solution of acryloyl chloride (0.035 ml, 0.44 mmol) in CH ₂ Cl ₂ (1 ml) at 0°C was added to a mixture of 2-{[5-amino-4-(2-dimethylaminoethylmethylamino)-2-methoxyphenyl]amino }-4-(1-methylindol-3yl)pyrimidin-5-carbonitrile (Intermediate 102, 171 mg, 0.36 mmol) and DIPEA (0.120 ml, 0.73 mmol) in CH ₂ Cl ₂ (3 ml) , then the mixture was stirred at 0°C for 1 hour. The mixture was then diluted with CH ₂ Cl ₂ , washed twice with sat. NaHCO ₃ and then water, then dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 0-5% methanol ammonia in CH ₂ Cl ₂ gave the title compound (68 mg, 36%) as a yellow solid.

^1H NMR (100°C): 2.22 (6H, s), 2.40 (2H, t), 2.76 (3H, s), 2.98 (2H, t), 3.77 (3H, s), 3.90 (3H, s) , 5.69 (1H, dd), 6.17 (1H, dd), 6.40 (1H, dd), 7.02-7.06 (2H, m), 7.21-7.25 (1H, m), 7.49 (1H, d), 8.23 (1H , d), 8.45 (1H, s), 8.47 (1H, s), 8.63 (1H, s), 8.86 (1H, s), 9.59 (1H, s); m/z: ES ⁺ MH ⁺ 525.32.

Example 30 prop-2-enamide.

A solution of acryloyl chloride (53.4 mg, 0.59 mmol) in CH ₂ Cl ₂ (1 ml) was added dropwise to the stirred mixture of 4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxy-N- [4-(1-methylindol-3yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 103, 270 mg, 0.59 mmol) and DIPEA (0.112 ml,

0.65 mmol) in CH ₂ Cl ₂ (10 ml), which was cooled in an ice/water bath. The mixture was stirred for 1.5 h and then diluted with CH ₂ Cl ₂ (25 ml) and washed with sat. NaHCO3 (50 ml). The aqueous washes were extracted with CH ₂ Cl ₂ (2x25 ml). The combined organic solutions were then dried (MgSO ₄ ) and concentrated in vacuo. As a result of purification by FCC eluting with 0-4% 7N. methanolic ammonia in CH2Cl2 gave the title compound mixed together with the diacylated material. This material was dissolved in CH ₂ Cl ₂ and triturated with diethyl ether. The resulting precipitate was collected by filtration, washed with diethyl ether (10 ml) and air dried to give the crude product (120 mg) as a yellow solid. This solid was purified by crystallization from CH ₃ CN to give the title compound (47 mg, 0.092 mmol, 16%) as a yellow solid. All residues were combined, concentrated in vacuo and crystallized from CH ₃ CN to give a second batch of the title compound (26 mg, 0.051 mmol, 9%) as a yellow solid. The total yield of the title compound was 73 mg, 24%.

1H NMR (CDCl ₃ ): 1.87-1.99 (1H, m), 2.11-2.24 (1H, m), 2.30 (6H, s), 2.83-2.95 (1H, m), 3-3.19 (4H, m), 3.88 (3H, s), 3.99 (3H, s), 5.75 (1H, dd), 6.34 (1H, dd), 6.44 (1H, dd), 6.79 (1H, s), 7.20 (1H, d), 7.23 -7.32 (2H, m) is partially hidden by the CDCl ₃ peak, 7.37-7.42 (1H, m), 7.67 (1H, s), 8.08 (1H, d), 8.38 (1H, d), 8.46 (1H, s), 9.00 (1H, s), 9.71 (1H, s); m/z: ES+MH+ 512.26.

Example 31. No.{5-[(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-4-methoxy-2[methyl-(2-morpholine-4 -ylethyl)amino1phenyl}prop-2-enamide.

Acryloyl chloride (0.413 ml, 1M in THF, 0.41 mmol) under N2 at -10°C over a period of 2 min was added dropwise to a suspension of A-(5-chloro-4-pyrazolo[1,5-a]pyridine -3-ylpyrimidin-2-yl)-5methoxy-H1-methyl-NG(2-morpholin-4-ylethyl)benzene-1,2,4-triamine (Intermediate 105, 298 mg, 0.59 mmol) and DIPEA (0.153 ml, 0.88 mmol) in THF (5 ml). The mixture was stirred at 0°C for 10 min and then allowed to warm to room temperature. within 20 min. The mixture was again cooled to -10°C and additional acryloyl chloride (0.103 ml, 1 M in THF, 0.103 mmol) was added dropwise. The suspension was stirred at 0°C for an additional 10 min, then allowed to warm to room temperature. within 20 min. The mixture was then concentrated in vacuo and the residue was dissolved in CH2Cl2 (5 ml). This solution was washed with sat. NaHCO3 (2 ml), dried (MgSO4) and concentrated in vacuo. As a result of purification by FCC eluting with 1.5-7% 7N. methanol ammonia in CH ₂ Cl ₂ to obtain a resin. This resin was dissolved in EtOAc (1 ml) and diethyl ether (approximately 1 ml) was added just until the end of oiling. The mixture was then stirred for 3 days, filtered and the collected solid was dried by aspiration to obtain the title compound (193 mg, 59%) as a cream-colored crystalline solid.

1H NMR: 2.29-2.38 (4H, m), 2.41 (2H, t), 2.74 (3H, s), 3.03 (2H, t), 3.49-3.61 (4H, m), 3.78 (3H, s), 5.72 (1H, d), 6.18 (1H, m), 6.60 (1H, m), 7.00 (1H, s), 7.10 (1H, m), 7.27-7.38 (1H, m), 8.25 (1H, s), 8.40 (2H, m), 8.65 (1H, s), 8.82 (1H, d), 8.95 (1H, s), 9.28 (1H, s); m/z: ES ⁺ MH ⁺ 563.

Example 32 -methylpiperazin-1-yl)ethyl]amino}phenyl)prop-2-enamide.

A solution of acryloyl chloride (0.028 ml, 0.35 mmol) in CH ₂ Cl ₂ (1 ml) under N2 was added dropwise to the stirred mixture of N ⁴ -(5-chloro-4-pyrazolo[1,5-a]pyridine-3 - ilpyrimidin-2-yl)-5-methoxy-N ¹ -methyl

- 34 046985

X-[2-(4-methylpiperazin-1-yl)ethyl]benzene-1,2,4-triamine (Intermediate 107, 0.174 g, 0.33 mmol) in CH ₂ Cl ₂ (2.5 ml). The mixture was then stirred at room temperature. for 1 hour and then diluted with CH ₂ Cl ₂ (25 ml). This solution was washed with sat. NaHCO ₃ (25 ml) and the aqueous wash solution were extracted with CH ₂ Cl ₂ (20 ml). The combined organic solutions were dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 0-8% CH ₃ OH in CH ₂ Cl ₂ gave the title compound (0.12 g, 63%) as a beige foam.

^1H NMR ( _CDCl3 ): 2.31 (3H, s), 2.35-2.6 (10H, m), 2.67 (3H, s), 3.00 (2H, t), 3.88 (3H, s), 5.64-5.82 (1H , m), 6.31-6.50 (2H, m), 6.79 (1H, s), 6.91 (1H, t), 7.29 (1H, t), 7.48 (1H, s), 8.47 (1H, s), 8.54 ( 2H, t), 8.94 (1H, s), 9.15 (1H, s), 9.38 (1H, s); m/z: ES+MH+ 576.59.

Example 33. No. (4-Methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}-2-{4-methylpiperazin1-yl}phenyl)prop-2-enamide.

A solution of acryloyl chloride (58.4 mg, 0.64 mmol) in CH ₂ Cl ₂ (1 ml) was added dropwise to the mixture of 4methoxy-N'-[4-(1-methylindol-3-yl)pyrimidin-2-yl] -6-(4-methylpiperazin-1-yl)benzene-1,3-diamine (Intermediate 110, 286 mg, 0.64 mmol) and DIPEA (0.134 ml, 0.77 mmol) in CH ₂ Cl ₂ (20 ml), which was cooled in an ice/water bath. The mixture was stirred for 1.5 hours at 0°C. Additional DIPEA (30 μl) was added, then additional acryloyl chloride (20 mg) was added dropwise as a solution in CH ₂ Cl ₂ (1 ml). This mixture was stirred for 2 hours and then diluted with CH ₂ Cl ₂ (50 ml). This solution was washed with sat. NaHCO ₃ solution (2x25 ml) and then the combined aqueous washes were extracted with CH ₂ Cl ₂ (2x25 ml). The combined organic solutions were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The resulting resin was triturated with diethyl ether to obtain a solid, which was collected by filtration and dried in vacuo. As a result of purification by FCC eluting with 0-8% 7N. methanolic ammonia in CH ₂ Cl ₂ and trituration with diethyl ether (with a few drops of CHO ₃ H) gave the title compound (55 mg, 17%) as a light gray solid.

^1H NMR: 2.27 (3H, s), 2.53-2.59 (4H, m), 2.85-2.91 (4H, m), 3.87 (3H, s), 3.91 (3H, s), 5.75 (1H, d), 6.24 (1H, d), 6.67 (1H, dd), 6.89 (1H, s), 7.15-7.28 (3H, m), 7.53 (1H, d), 7.89 (1H, s), 8.28 (1H, d) , 8.32 (1H, d), 8.58 (1H, s), 8.81 (1H, s), 9.07 (1H, s); m/z: ES ⁺ MH ⁺ 498.58.

Example 34 -2-enamid.

A solution of acryloyl chloride (0.049 ml, 0.60 mmol) in CH ₂ Cl ₂ (0.5 ml) was added dropwise to the mixture of N-[5-χλορ-4-(1-methylindol-3-yl)pyrimidin-2-yl ]-4-(3-dimethylaminoazetidin-1-yl)-6-methoxybenzene1,3-diamine (Intermediate 112, 260 mg, 0.54 mmol) in CH ₂ Cl ₂ (9 ml). This mixture was stirred for 1 hour and then loaded onto an SCX column. The column was washed with CH3OH and the target product was then eluted from the column using 2M methanol ammonia. The appropriate fractions were concentrated in vacuo to give a brown gum. Purification by FCC eluting with 1-10% CH3OH in CH2Cl2 (containing 1% concentrated aqueous ammonia) and trituration with CH3OH (0.5 ml) using an ultrasonic bath for 2 min gave the title compound (214 mg, 74%) as a yellow solid.

^1H NMR: 2.10 (6H, s), 3.03-3.14 (1H, m), 3.59 (2H, t), 3.77 (3H, s), 3.90 (3H, s), 3.97 (2H, t), 5.66 ( 1H, dd), 6.16 (1H, dd), 6.23 (1H, s), 6.46 (1H, dd), 7.12 (1H, t), 7.23 (1H, t), 7.44-7.54 (2H, m), 8.20 -8.38 (3H, m), 8.51 (1H, s), 9.21 (1H, s); m/z: ES+MH+ 532.

Example 35 2-enamid.

A solution of acryloyl chloride (0.024 ml, 0.30 mmol) in CH ₂ Cl ₂ (1 ml) was added dropwise to a stirred solution of 4-(3-dimethylaminoazetidin-1-yl)-6-methoxy-N-[5-methyl-4 -(1-methylindol-3yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 114, 130 mg, 0.28 mmol) in CH ₂ Cl ₂ (5 ml), which was cooled in an ice bath brine to approximately 0°C. The mixture was stirred for 1 hour, then diluted with CH2Cl2 (50 ml) and CH3OH (until the resulting suspension was completely dissolved). This solution was then washed with sat. NaHCO3 (100 ml), which was diluted with water (10 ml). The aqueous wash solution was then extracted with CH ₂ Cl ₂ (2x50 ml) and the combined organic solutions were dried (MgSO4) and concentrated in vacuo. As a result of purification by FCC eluting with 0-5% 7N. methanolic ammonia in CH2Cl2 gave a dark brown solid. This solid was heated in CH3CN and isolated by suction filtration to give the title compound (45 mg, 31%) as a pale brown solid. The mother liquor was concentrated in vacuo and also saved as a second batch of the title compound (30 mg, 21%) as a darker brown solid. The total yield of the title compound was 75 mg, 52%.

^1H NMR: 2.08 (6H, s), 2.34 (3H, s), 3-3.1 (1H, m), 3.55 (2H, t), 3.83 (3H, s), 3.88 (3H, s), 3.93 ( 2Н, t), 5.65 (1H, dd), 6.15 (1H, dd), 6.24 (1H, s), 6.44 (1H, dd), 7.13 (1H, t), 7.21 (1H, t), 7.47 (1H , d), 7.66 (1H, s), 7.81 (1H, s), 7.99 (1H, s), 8.17 (1H, s), 8.37 (1H, d), 9.19 (1H, s); m/z: ES ⁺ MH ⁺ 512.14.

Example 36. No. (2-{3-Dimethylaminoazetidin-1-yl}-4-methoxy-5-{ [4-(1-methylindol-3-yl)pyrimidin- 35 046985

2-yl]amino}phenyl)prop-2-enamide.

A solution of acryloyl chloride (0.044 ml, 0.54 mmol) in CH ₂ Cl ₂ (1 ml) was added dropwise to a mixture of 4-(3-dimethylaminoazetidin-1-yl)-6-methoxy-N-[4-(1-methylindole -3-yl)pyrimidin-2-yl]benzene-1,3diamine (Intermediate 116, 240 mg, 0.54 mmol) and DIPEA (0.104 ml, 0.60 mmol) in CH ₂ Cl ₂ (5 ml), which was cooled in an ice/water bath. The mixture was stirred for 1 hour and then washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. As a result of purification by FCC eluting with 0-2% 7N. methanolic ammonia in CH ₂ Cl ₂ and trituration with diethyl ether and washing the resulting solid with a small volume of CH ₃ OH gave the title compound (38 mg, 14%) as a yellow solid.

^1H NMR: 2.10 (6H, s), 3.08 (1H, t), 3.56 (2H, t), 3.86 (3H, s), 3.89 (3H, s), 3.96 (2H, t), 5.69 (1H, dd), 6.18-6.29 (2H, m), 6.52 (1H, dd), 7.14 (1H, d), 7.17-7.28 (2H, m), 7.51 (1H, d), 7.75 (1H, s), 7.98 (1H, s), 8.26 (1H, d), 8.34 (2H, d), 9.29 (1H, s); m/z: ES ⁺ MH ⁺ 498.44.

Example 37 2-enamid.

A solution of acryloyl chloride (0.057 ml, 0.70 mmol) in CH ₂ Cl ₂ (1 ml) was added dropwise to the stirred solution of N-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl] -4-(3-dimethylaminoazetidin-1-yl)-6methoxybenzene-1,3-diamine (Intermediate 118, 310 mg, 0.67 mmol) and DIPEA (0.127 ml, 0.73 mmol) in CH ₂ Cl ₂ ( 40 ml), which was cooled in an ice/water bath to 0°C. The mixture was stirred in an ice/water bath for 1 hour and then allowed to warm to room temperature. The mixture was then kept at room temperature. for 18 hours and then diluted with CH ₂ Cl ₂ (100 ml). This solution was then washed with sat. NaHCO ₃ (200 ml) and aqueous wash solution were extracted with CH ₂ Cl ₂ (2x100 ml). The combined organic solutions were dried (MgSO ₄ ) and concentrated in vacuo.

As a result of purification by FCC eluting with 0-5% 7N. methanolic ammonia in CH2Cl2 gave the title compound along with the impurity (172 mg, 50%) as a pale yellow solid. 120 mg of this material was purified by crystallization from CH3CN to give the title compound (85 mg, 0.164 mmol) as a yellow solid without obvious traces of impurities by NMR analysis. The crystallization mother liquor and additional crude fraction from FCC (containing a 75:25 product:starting material mixture) were combined, concentrated in vacuo, and purified by crystallization from CH ₃ CN to provide additional title compound (40 mg, 12%) in as a yellow-brown solid.

1H NMR: 2.09 (6H, s), 3.03-3.12 (1H, m), 3.58 (2H, t), 3.78 (3H, s), 3.96 (2H, t), 5.66 (1H, dd), 6.16 (1H , dd), 6.25 (1H, s), 6.46 (1H, dd), 7.07 (1H, t), 7.16 (1H, t), 7.45 (1H, d), 7.48 (1H, s), 8.24 (1H, s), 8.27-8.31 (1H, br s), 8.31 (1H, s), 8.46 (1H, d), 9.22 (1H, s), 11.79 (1H, s); m/z: ES+MH+ 518.23.

Example 38 -4-methoxyphenyl}prop-2-enamide.

A solution of acryloyl chloride (0.027 ml, 0.33 mmol) in CH ₂ Cl ₂ (1 ml) was added dropwise to the mixture of 2({5-amino-4-[(3R)-3-(dimethylamine)pyrrolidin-1-yl] -2-methoxyphenyl}amino)-4-(pyrazolo[1,5a]pyridin-3-yl)pyrimidin-5-carbonitrile (Intermediate 120, 155 mg, 0.33 mmol) and DIPEA (0.063 ml, 0.36 mmol) in CH ₂ Cl ₂ (10 ml), which was cooled in an ice/water bath. The mixture was stirred for 2 hours and then washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. As a result of purification by FCC eluting with 2% 7N. methanol ammonia in CH ₂ Cl ₂ , foam was obtained. Concentration from CH ₃ OH/CH ₂ Cl ₂ gave a solid which was triturated in diethyl ether and collected by filtration to give the title compound (95 mg, 55%) as a yellow solid.

1H NMR (100°C): 1.82 (1H, dq), 2.08 (1H, ddd), 2.22 (6H, s), 2.8-2.89 (1H, m), 3.19-3.45 (4H, m), 3.78 (3H , s), 5.63 (1H, dd), 6.16 (1H, dd), 6.44 (1H, dd), 6.61 (1H, s), 7.12 (1H, td), 7.34-7.46 (1H, m), 7.54 ( 1H, s), 8.33 (1H, d), 8.64 (1H, s), 8.77 (1H, d), 8.90 (2H, s), 8.96 (1H, s); m/z: ES ⁺ MH ⁺ 524.57.

Example 39. No.{5-[(5-Cyano-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-2-[2-dimethylaminoethylmethylamino]-4-methoxyphenyl} prop-2-enamid.

A solution of acryloyl chloride (0.087 mL, 1 M, THF, 0.09 mmol) was added dropwise to a mixture of 2-{[5amino-4-(2-dimethylaminoethylmethylamino)-2-methoxyphenyl]-amino}-4-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidine-5-carbonitrile (Intermediate 121, 0.036 g, 0.08 mmol) and DIPEA (0.017 ml, 0.09 mmol) in THF (5 ml), which was cooled to 0°C . The mixture was stirred at 0°C for 3 hours, then concentrated in vacuo. Purification by FCC eluting with 0-20% CH ₃ OH in CH 2 Cl 2 provided a crude product that appeared to contain the DIPEA hydrochloride salt. The material was dissolved in CH ₂ Cl ₂ (10 ml) and stirred with sat. NaHCO ₃ solution (10 ml). The phases were separated and the organic solution was concentrated in vacuo to give the title compound (24 mg, 60%) as a yellow gum.

1H NMR (CDCl ₃ ): 2.22 (6H, s), 2.26 (2H, dd), 2.67 (3H, d), 2.77-2.86 (2H, m), 3.81 (3H, s), 5.61 (1H, dd) , 6.16-6.35 (2H, m), 6.76 (1H, s), 6.88 (1H, d), 7.23 (1H, s), 7.65 (1H, s), 8.50 (2H, dd), 8.59 (1H, s ), 9.02 (1H, s), 9.28 (1H, s), 10.08 (1H, s); m/z: ES+MH+ 512.29.

- 36 046985

Example 40 methoxyphenyl}prop-2-enamide.

A solution of acryloyl chloride (0.025 ml, 0.31 mmol) in CH ₂ Cl ₂ (1 ml) was added dropwise to the stirred solution of 2-{[5-amino-4-(3-dimethylaminoazetidin-1-yl)-2-methoxyphenyl] amino}-4pyrazolo[1,5-a]pyridin-3-ylpyrimidin-5-carbonitrile (Intermediate 122, 136 mg, 0.30 mmol) in CH ₂ Cl ₂ (15 ml), which was cooled in an ice bath to ca. 0°C. The mixture was stirred for 1 hour and then diluted with CH ₂ Cl ₂ (50 ml) and methanol (until the suspension was completely dissolved). This solution was then washed with sat. NaHCO ₃ (100 ml), which was diluted with water (10 ml). The aqueous wash solution was then extracted with CH ₂ Cl ₂ (2x50 ml) and the combined organic solutions were dried (MgSO ₄ ) and concentrated in vacuo. As a result of purification by FCC eluting with 0-5% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (136 mg, 89%) as a yellow solid.

^1H NMR: 2.10 (6H, s), 3.05-3.13 (1H, m), 3.62 (2H, t), 3.74 (3H, s), 4.00 (2H, s), 5.67 (1H, d), 6.17 ( 1H, d), 6.27 (1H, s), 6.45 (1H, dd), 7.16 (1H, br s), 7.25 (1H, s), 7.42 (1H, br s), 7.95 (1H, br s), 8.68 (1H, s), 8.87 (1H, br s), 8.91 (1H, s), 9.28 (1H, s), 9.32 (1H, br s); m/z: ES ⁺ MH ⁺ 510.18.

Example 41 {[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide.

Acryloyl chloride (41.3 mg, 0.46 mmol) in THF (1 ml) was added dropwise to the stirred solution of 4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo [3,4-b]pyrrol-1-yl]-6-methoxy-N-[4-(1methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 123, 195 mg , 0.42 mmol) in THF (3 ml), cooled in an ice/methanol bath to approximately -15°C. When acryloyl chloride was added slowly, a precipitate immediately formed. The mixture was stirred for 1 hour while gradually heating to 0°C. The mixture was then diluted with CH2Cl2 (50 ml) and washed with sat. NaHCO3 (50 ml). The resulting aqueous solution was extracted with CH ₂ Cl ₂ (2x25 ml). The combined organic solutions were dried (MgSO4) and concentrated on silica. As a result of purification by FCC eluting with 0-5% 7N. methanolic ammonia in CH2Cl2 and after concentrating the appropriate fractions in vacuo, the crude solid product was obtained. This solid was dissolved in a minimal amount of hot CH2Cl2 and triturated with diethyl ether to give the title compound (115 mg, 53%) as a white solid.

^1H NMR ( _CDCl3 ): 1.77-1.96 (2H, m), 2.15-2.26 (1H, m), 2.29 (3H, s), 2.26-2.37 (1H, m), 2.73 (1H, d), 2.80 (1H, d), 2.83-2.90 (1H, m), 2.95 (1H, td), 3.21 (1H, t), 3.57-3.68 (1H, m), 3.88 (3H, s), 4.00 (3H, s ), 5.685.74 (1H, m), 6.45 (2H, d), 6.81 (1H, s), 7.20 (1H, d), 7.23-7.31 (2H, m) partially hidden under the CDCl ₃ signal, 7.37-7.43 (1H, m), 7.71 (1H, s), 8.02-8.10 (1H, m), 8.38 (1H, d), 9.09 (1H, s), 9.46 (1H, s), 9.85 (1H, s); m/z: ES ⁺ MH ⁺ 524.25.

Example 42 2-yl] amino } phenyl)prop-2-enamide.

A solution of acryloyl chloride (0.354 ml, 4.35 mmol) in CH ₂ Cl ₂ (5 ml) was added dropwise to the mixture of Y-(2-dimethylaminoethyl)-5-methoxy-H1-methyl-H ⁴ -[4-(4, 5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3yl)pyrimidin-2-yl]benzene-1,2,4-triamine (intermediate 125, 1.9 g, 4.35 mmol) in CH2Cl2 (100 ml), which was cooled in an ice/water bath. The resulting mixture was stirred for 1 hour and then washed with sat. _NaHCO3 . The resulting organic solution was dried (Na ₂ SO ₄ ) and concentrated in vacuo. As a result of purification by FCC eluting with 1.5% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (1.069 g, 50%) as an oil which crystallized on standing to give a cream-colored crystalline solid. A number of later fractions from FCC, which were brown in color, were concentrated and re-chromatographed to give additional title compound (334 mg, 16%) as a pale brown oil that crystallized on standing to give a yellow-brown color. the color of a crystalline solid. Total yield: 1.403 g, 66%.

1H NMR: 1.69-1.77 (2H, m), 1.88-1.97 (2H, m), 2.21 (6H, s), 2.29 (2H, t), 2.71 (3H, s), 2.88 (2H, t), 3.02 (2H, t), 3.84 (3H, s), 4.09 (2H, t), 5.74 (1H, dd), 6.24 (1H, dd), 6.40 (1H, dd), 6.97-7.02 (2H, m), 7.87 (1H, s), 8.13 (1H, s), 8.31 (1H, d), 8.85 (1H, s), 10.08 (1H, s); m/z: ES+MH ⁺ 491.34.

Example 43 {[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2enamide.

A solution of acryloyl chloride (26 mg, 0.29 mmol) in THF (1 ml) was added dropwise to a stirred solution of 4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[ 3,4-b]pyrrol-1-yl]-6-methoxy-N-[4(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl ]benzene-1,3-diamine (Intermediate 132, 120 mg, 0.26 mmol) in THF (3 ml), which was cooled in an ice/methanol bath to approximately -15°C. The mixture was stirred for 1 hour, gradually heating to 0°C. The mixture was then diluted with CH2Cl2 (50 ml) and washed with sat. NaHCO3 (50 ml). The resulting aqueous wash solution was further extracted with CH ₂ Cl ₂ (2x25 ml) and the combined organic solutions were then dried

- 37 046985 (MgSO.-i) and concentrated in vacuo on silica. Partial purification was achieved using FCC, eluting with 0-5% 7N. methanolic ammonia in CH2C12, and the fractions containing the contaminated product were combined and concentrated in vacuo. As a result of purification by FCC eluting with 0-2% 7N. methanolic ammonia in CH2C12 and subsequent elution with 0-3% CH ₃ OH in CH2C12 gave the title compound (19 mg, 14%) as a cream colored foam.

1H NMR (CDC1 ₃ ): 1.82-1.97 (4H, m), 2.00-2.06 (2H, m), 2.13-2.24 (1H, s), 2.25-2.39 (1H, m), 2.29 (3H, s), 2.67-2.98 (4H, m), 3.17-3.26 (3H, m), 3.66 (1H, br s), 3.86 (3H, s), 4.18 (2H, t), 5.64-5.71 (1H, m), 6.30 -6.47 (2H, m), 6.78 (1H, s), 6.81 (1H, d), 7.44 (1H, s), 8.06 (1H, s), 8.34 (1H, d), 9.24 (1H, s), 9.40 (1H, s); m/z: ES+MH+ 515.15.

Example 44 -3 -yl)pyrimidin-2-yl] amino } phenyl)prop-2-enamide.

A solution of acryloyl chloride (32 mg, 0.36 mmol) in CH2C12 (1 ml) was added dropwise to a stirred solution of 4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxy-N-[4-(4 ,5,6,7tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 134, 152 mg, 0.34 mmol) in CH ₂ Cl ₂ (15 ml), which was cooled in an ice/water bath. The solution was stirred for 10 minutes while cooling with an ice bath and then allowed to warm to RT, after which it was stirred for 1 hour. The mixture was then diluted with CH2C12 and washed with sat. NaHCO ₃ and then brine. The organic solution was then dried (MgSO ₄ ) and concentrated in vacuo. As a result of purification by FCC eluting with 0-5% 7N. methanolic ammonia in CH2C12 and trituration with diethyl ether gave the crude product (100 mg) as a beige solid. CH3CN (approximately 3 ml) was then added to the crude product and the resulting suspension was stirred at 50°C for 4 hours. After cooling, the other room temperature. the suspended solid was collected by filtration, washed with CH3CN and dried at 45°C overnight to give the title compound (72 mg, 42%) as a yellow solid.

1H NMR: 1.68-1.81 (3H, m), 1.89-1.98 (2H, m), 2.03-2.11 (1H, m), 2.17 (6H, s), 2.66-2.74 (1H, m), 3.003.05 ( 2H, m), 3.13-3.21 (3H, m), 3.31-3.38 (1H, m), 3.86 (3H, s), 4.09 (2H, t), 5.70 (1H, dd), 6.21 (1H, dd) , 6.48-6.56 (2H, m), 6.96 (1H, d), 7.72 (1H, s), 8.03 (2H, d), 8.27 (1H, d), 9.30 (1H, s); m/z: ES ⁺ MH ⁺ 503.67.

Example 45. No(4-Methoxy-2-{1-methyl-3,6-dihydro-2H-pyridin-4-yl}-5-{ [4-(4,5,6,7-tetrahydropyrazolo [1, 5-a] pyridin-3 -yl) pyrimidin-2-yl] amino } phenyl) prop-2-enamide.

A solution of acryloyl chloride (30 µl, 0.37 mmol) in CH2C12 (2 ml) was added dropwise over 5 min to 4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl) -N'-[4-(4,5,6,7-tetrahydropyrazolo[1,5a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 136, 154 mg, 0 .36 mmol) in CH2C12 (5 ml), which was cooled in an ice/CH ₃ OH bath. The mixture was then stirred for 0.5 h. The mixture was then diluted with 10% CH3OH/CH2C12 and the resulting solution was washed with sat. NaHCO3, dried (MgSO4) and then concentrated in vacuo. Purification by FCC eluting with 0-10% methanolic ammonia in CH2C12 and trituration with diethyl ether/heptane provided the title compound (104 mg, 60%) as a pale yellow solid.

1H NMR: 1.76-1.84 (2H, m), 1.91-1.98 (2H, m), 2.27 (3H, s), 2.32-2.39 (2H, m), 2.48-2.56 (2H, m), 2.962.99 ( 2H, m), 3.08 (2H, t), 3.90 (3H, s), 4.11 (2H, t), 5.65-5.76 (2H, m), 6.21 (1H, d), 6.49 (1H, dd), 6.84 (1H, s), 7.07 (1H, d), 7.84 (1H, s), 8.10 (1H, s), 8.32-8.37 (2H, m), 9.33 (1H, s); m/z: ES+MH+ 486.73.

Example 46 2-yl]amino}phenyl)prop-2-enamide.

A solution of acryloyl chloride (22.5 mg, 0.25 mmol) in CH2C12 (1 ml) was added dropwise to a stirred solution of 4-(3-dimethylaminoazetidin-1-yl)-6-methoxy-H-[4-(4.5 ,6,7-tetrahydropyrazolo[1,5a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 139, 108 mg, 0.25 mmol) in CH2C12 (12 ml), which was cooled in an ice/water bath. The solution was stirred for 10 minutes while cooling by bath, then allowed to warm to room temperature. and then stirred for 1 hour. The mixture was then diluted with CH ₂ C1 ₂ and washed with sat. NaHCO ₃ , brine and then dried (MgSO ₄ ). As a result of purification by FCC eluting with 0-5% 7N. methanolic ammonia in CH ₂ C1 ₂ and trituration with diethyl ether gave the title compound (56 mg, 46%) as a brown solid.

1H NMR: 1.75-1.82 (2H, m), 1.90-1.97 (2H, m), 2.08 (6H, s), 2.98-3.09 (3H, m), 3.54 (2H, t), 3.85 (3H, s) , 3.93 (2H, t), 4.09 (2H, t), 5.69 (1H, dd), 6.18-6.25 (2H, m), 6.49 (1H, dd), 6.95 (1H, d), 7.70 (1H, s ), 7.89 (1H, s), 8.03 (1H, s), 8.26 (1H, d), 9.24 (1H, s); m/z: ES ⁺ MH ⁺ 489.63.

Example 47. No(4-Methoxy-2-{8-methyl-2,8-diazaspiro[3.4]octan-2-yl}-5-{[4-(4,5,6,7-tetrahydropyrazolo [1, 5-a] pyridin-3 -yl) pyrimidin-2-yl] amino } phenyl) prop-2-enamide.

A solution of acryloyl chloride (42 µl, 0.52 mmol) in CH2C12 (1 ml) was added dropwise to 4-methoxy-6(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-N'-[ 4-(4,5,6,7-tetrahydropyrazolo-[1,5-a]pyridin-3yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 141, 240 mg, 0.52 mmol) and DIPEA (0.099 ml, 0.57 mmol) in CH ₂ C1 ₂ (10 ml), which was cooled in an ice/water bath. The mixture was stirred for 1 hour and then washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. As a result

- 38 046985 purification by FCC eluting with 2% 7N. methanolic ammonia in CH2C12 trituration with CH3CN gave the title compound (135 mg, 50%) as a yellow solid.

1H NMR: 1.61-1.74 (2H, m), 1.73-1.85 (2H, m), 1.87-1.99 (2H, m), 2.03 (2H, t), 2.35 (3H, s), 2.61 (2H, t) , 3.01 (2H, t), 3.60 (2H, d), 3.84 (3H, s), 3.89 (2H, d), 4.09 (2H, t), 5.70 (1H, d), 6.14-6.30 (2H, m ), 6.47 (1H, dd), 6.95 (1H, d), 7.73 (1H, s), 7.83 (1H, s), 8.05 (1H, s), 8.26 (1H, d), 9.26 (1H, s) ; m/z: ES+MH+ 515.7.

Example 48 ]amino}phenyl)prop-2-enamide.

A solution of acryloyl chloride (37 µl, 0.45 mmol) in CH ₂ Cl ₂ (2.32 ml) was added dropwise over 5 min to 4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridine -4-yl)-No-[4-( 1 -methylindol-3-yl)pyrimidin-2yl]benzene-1,3-diamine (Intermediate 143, 189 mg, 0.43 mmol) in CH ₂ Cl ₂ ( 5.8 ml), which was cooled in an ice/CH3OH bath. The mixture was stirred for 0.5 h and then diluted with 10% CH ₃ OH/CH ₂ Cl ₂ . The resulting solution was washed with sat. NaHCO ₃ , dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 0-20% CH3OH in CH ₂ Cl ₂ and trituration with diethyl ether provided the title compound (67 mg, 32%) as a pale yellow solid.

^1H NMR: 2.29 (3H, s), 2.36-2.41 (2H, m), 2.53-2.58 (2H, m), 2.98-3.02 (2H, m), 3.90 (3H, s), 3.91 (3H, s ), 5.69-5.73 (2H, m), 6.22 (1H, dd), 6.52 (1H, dd), 6.86 (1H, s), 7.20-7.28 (3H, m), 7.52-7.55 (1H, m), 7.88 (1H, s), 8.33-8.37 (2H, m), 8.43 (1H, s), 8.45 (1H, s), 9.34 (1H, s); m/z: ES ⁺ MH ⁺ 495.70.

Example 49. No. (4-Methoxy-2-{8-methyl-2,8-diazaspiro[3.4]octan-2-yl}-5-{ [4-(1-methylindol-3yl)pyrimidin-2-yl] amino}phenyl)prop-2-enamide.

A solution of acryloyl chloride (24 µl, 0.30 mmol) in CH ₂ Cl ₂ (1 ml) was added dropwise to 4-methoxy-6(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-No. -[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 146, 140 mg, 0.30 mmol) and DIPEA (57 µL, 0.33 mmol) in CH ₂ Cl ₂ (10 ml), which were cooled in an ice/water bath. The mixture was stirred for 1 hour and then washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. As a result of purification by FCC eluting with 2% 7N. methanolic ammonia in CH ₂ Cl ₂ and trituration with CH3CN gave the title compound (43 mg, 28%) as a beige solid.

1H NMR: 1.63-1.76 (2H, m), 2.00-2.10 (2H, m), 2.38 (3H, s), 2.63 (2H, t), 3.64 (2H, d), 3.86 (3H, s), 3.89 (3H, s), 3.93 (2H, d), 5.70 (1H, dd), 6.21 (1H, dd), 6.26 (1H, s), 6.50 (1H, dd), 7.13 (1H, d), 7.16- 7.29 (2H, m), 7.51 (1H, d), 7.73 (1H, s), 7.93 (1H, s), 8.26 (1H, d), 8.31-8.39 (2H, m), 9.24 (1H, s) ; m/z: ES ⁺ MH ⁺ 524.7.

Example 50 )prop-2-enamide.

A solution of acryloyl chloride (1M in CH ₂ Cl ₂ , 0.36 ml, 0.36 mmol) at -10°C over a period of 2 minutes under N2 was added dropwise to a solution of 4-[(3S)-3-dimethylaminopyrrolidine- 1-yl]-6methoxy-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 148, 183 mg, 0.40 mmol) in CH ₂ Cl ₂ (5 ml). The resulting mixture was stirred at 0°C for 10 min and then left to warm to room temperature. within 20 min. The mixture was then washed with sat. NaHCO3 (2 ml), dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 3-25% CH3OH in CH ₂ Cl ₂ gave an oil which later crystallized. This solid was triturated and washed with EtOAc (3 mL) to give the title compound (67 mg, 33%) as a pale yellow solid.

1H NMR: 1.77 (1H, m), 2.08 (1H, s), 2.18 (6H, s), 2.72 (1H, m), 3.17 (1H, s), 3.21 (2H, d), 3.32-3.45 (1H , m), 3.87 (3H, s), 3.89 (3H, s), 5.70 (1H, d), 6.22 (1H, d), 6.48-6.58 (1H, m), 6.59 (1H, s), 7.20 ( 3H, m), 7.51 (1H, d), 7.76 (1H, s), 8.17 (1H, s), 8.28 (1H, d), 8.32 (1H, d), 8.39 (1H, s), 9.33 (1H , s); m/z: ES+MH+ 512.7.

Example 51. No.{4-Methoxy-2-[1-methyl-3,6-dihydro-2H-pyridin-4-yl]-5-[(4-pyrazolo[1,5-a]pyridin3-ylpyrimidin-2 -yl)amino]phenyl}prop-2-enamide.

A solution of acryloyl chloride (20 µl, 0.25 mmol) at -5°C for a period of 1 min under N2 was added dropwise to 4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridinium- 4-yl)-N'-(4-pyrazolo[1,5a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine (Intermediate 150, 180 mg,

0.42 mmol) and triethylamine (73 µl, 0.53 mmol) in THF (3 ml). The resulting mixture was stirred at 0°C for 0.25 hours. The reaction was determined to be incomplete, so additional acryloyl chloride (10 μL, 0.125 mmol) was added dropwise and the mixture was stirred at 0°C for an additional 15 minutes. The mixture was then concentrated in vacuo and the resulting residue was dissolved in CH ₂ Cl ₂ (5 ml) plus a few drops of CH3OH. This solution was washed with sat. NaHCO ₃ (2 ml), dried (MgSO ₄ ) and filtered through a pad of 1 g silica, eluting with 4:1 CH ₂ Cl ₂ -CH ₃ OH. The eluent, which contained the target product, was concentrated in vacuo. Purification by FCC eluting with 5-20% CH3OH in CH ₂ Cl ₂ provided the title compound (31 mg, 14%) as a cream-colored crystalline solid.

1H NMR: 2.33 (3H, s), 2.40 (2H, s), 2.57 (2H, d), 3.03 (2H, s), 3.89 (3H, s), 5.70 (2H, m), 6.17 (1H, m ), 6.46 (1H, m), 6.88 (1H, s), 7.09 (1H, t), 7.32 (1H, d), 7.47 (1H, t), 8.12 (1H, s), 8.21 (1H, s) , 8.39 (1H, d), 8.51 (1H, d), 8.81 (2H, m), 9.36 (1H, s); m/z: ES ⁺ MH ⁺ 482.

Example 52. N-{2-[(3R)-3-Dimethylaminopyrrolidin-1-yl]-4-methoxy-5-[(4-pyrazolo[1,5-a]pyridin- 39 046985

-ylpyrimidin-2-yl)amino]phenyl}prop-2-enamide.

A solution of acryloyl chloride (64 µl, 0.79 mmol) in CH ₂ Cl ₂ (4 ml) was added dropwise over 10 min to 4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxy-N- (4-pyrazolo[1,5-a]pyridin-3ylpyrimidin-2-yl)benzene-1,3-diamine (Intermediate 153, 336 mg, 0.76 mmol) in CH ₂ Cl ₂ (11 ml), which cooled in an ice/CH3OH bath. The mixture was stirred for 0.5 h and then diluted with 10% CH ₃ OH/CH ₂ Cl ₂ . The resulting solution was washed with saturated NaHCO3, dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 0-5% methanolic ammonia in CH ₂ Cl ₂ and trituration with diethyl ether gave the title compound (296 mg, 79%) as an orange solid.

^1H NMR: 1.70-1.81 (1H, m), 2.05-2.13 (1H, m), 2.18 (6H, s), 2.68-2.76 (1H, m), 3.17-3.27 (3H, m), 3.353.42 (1H, m), 3.84 (3H, s), 5.67 (1H, dd), 6.17 (1H, dd), 6.51 (1H, dd), 6.56 (1H, s), 7.05 (1H, dd), 7.21 ( 1H, d), 7.40-7.45 (1H, m), 7.84 (1H, s), 8.02 (1H, s), 8.30 (1H, d), 8.46 (1H, d), 8.76 (1H, s), 8.78 (1H, d), 9.35 (1H, s); m/z: ES ⁺ MH ⁺ 499.69.

Example 53. No. {2-(3-Dimethylaminoazetidin-1-yl)-4-methoxy-5-[(4-pyrazolo[1,5-a]pyridin-3ylpyrimidin-2-yl)amino]phenyl}prop-2 -enamid.

A solution of acryloyl chloride (49 µl, 0.60 mmol) in CH ₂ Cl ₂ (2.77 ml) was added dropwise over 5 min to 4-(3-dimethylaminoazetidin-1-yl)-6-methoxy-N-(4 -pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2yl)benzene-1,3-diamine (Intermediate 156, 246 mg, 0.57 mmol) in CH ₂ Cl ₂ (8.3 ml), which cooled in an ice/CH3OH bath. The mixture was stirred for 0.5 h and then diluted with 10% CH ₃ OH/CH ₂ Cl ₂ . The resulting solution was washed with sat. NaHCO ₃ , dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 0-5% methanolic ammonia in CH2Cl2 and trituration with diethyl ether gave the title compound (182 mg, 66%) as a yellow solid.

^1H NMR: 2.09 (6H, s), 3.04-3.12 (1H, m), 3.55-3.60 (2H, m), 3.83 (3H, s), 3.96 (2H, t), 5.67 (1H, dd), 6.18 (1H, dd), 6.26 (1H, s), 6.48 (1H, dd), 7.05 (1H, td), 7.20 (1H, d), 7.41-7.46 (1H, m), 7.71 (1H, s) , 8.00 (1H, s), 8.29 (1H, d), 8.43 (1H, br d), 8.75 (1H, s), 8.77 (1H, d), 9.29 (1H, s); m/z: ES ⁺ MH ⁺ 485.69.

Example 54. No. {2-[2-Dimethylaminoethyl-methylamino]-4-methoxy-5-[(4-pyrazolo[1,5-a]pyridin-3ylpyrimidin-2-yl)amino]phenyl}prop-2-enamide .

A solution of acryloyl chloride (63 µl, 0.78 mmol) in CH ₂ Cl ₂ (3.60 ml) was added dropwise over 5 minutes to N ¹ -(2-dimethylaminoethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2yl)benzene-1,2,4-triamine (Intermediate 158, 320 mg, 0.74 mmol) in CH ₂ Cl ₂ (10, 8 ml), which was cooled in an ice/CH3OH bath. The mixture was stirred for 0.5 h and then diluted with 10% CH3OH/CH2Cl2. The resulting solution was washed with sat. NaHCO3, dried (MgSO4) and concentrated in vacuo. Purification by FCC eluting with 0-5% methanolic ammonia in CH2Cl2 and trituration with diethyl ether gave the title compound (228 mg, 63%) as a pale pink solid.

1H NMR: 2.22 (6H, s), 2.33 (2H, t), 2.74 (3H, s), 2.91 (2H, t), 3.82 (3H, s), 5.73 (1H, dd), 6.19 (1H, dd ), 6.41 (1H, dd), 7.02-7.06 (2H, m), 7.25 (1H, d), 7.29-7.34 (1H, m), 8.17 (1H, s), 8.34 (1H, d), 8.44 ( 1H, d), 8.758.79 (2H, m), 8.82 (1H, s), 10.06 (1H, br s); m/z: ES ⁺ MH ⁺ 487.72.

Example 55 [(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-amino]phenyl]prop-2-enamide.

A solution of acryloyl chloride (13 mg, 0.14 mmol) in THF (1 ml) was added dropwise to a stirred solution of 4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[ 3,4-b]pyrrol-1-yl]-6-methoxy-N-(4pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine (Intermediate 160, 100 mg, 0.13 mmol) in THF (3 ml), which was cooled in an ice/CH3OH bath to approximately -15°C. The mixture was stirred for 1 hour and left to warm to -0°C. The mixture was then diluted with CH ₂ Cl ₂ (50 ml) and the resulting solution was washed with sat. NaHCO3 (50 ml). The aqueous solution was further extracted with CH ₂ Cl ₂ (2x25 ml) and the combined organic solutions were dried (MgSO ₄ ) and concentrated in vacuo on silica. As a result of partial purification by FCC eluting with 03.5% 7N. methanolic ammonia in CH2Cl2 gave some amount of the title compound. As a result of additional purification by FCC eluting with 0-1.5% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (33 mg, 49%) as a yellow solid.

1H NMR: 1.77 (1H, s), 1.94-2.15 (1H, m), 2.10 (3H, s), 2.29 (1H, d), 2.39-2.48 (1H, m), 2.87 (1H, s), 3.113 .20 (1H, m), 3.33-3.42 (2H, m),3.81 (3H, s),4.26-4.34 (1H, m),5.68 (1H, dd), 6.18 (1H, dd), 6.53 (1H , dd), 6.67 (1H, s), 7.04 (1H, td), 7.21 (1H, d), 7.36-7.43 (1H, m), 8.03 (1H, s), 8.08 (1H, s), 8.30 ( 1H, d), 8.42 (1H, d), 8.73-8.79 (2H, m), 9.41 (1H, s); m/z: ES'Mlll· 511.16.

Example 56 2-yl)amino]phenyl}prop-2-enamide.

A solution of acryloyl chloride (0.766 ml, 0.77 mmol, 1.0 M in CH ₂ Cl ₂ ) was added dropwise over 10 min to 4-methoxy-6-(8-methyl-2,8-diazaspiro[3.4]octane- 2-yl)-H'-(4-pyrazolo[1,5-a]pyridin-3ylpyrimidin-2-yl)benzene-1,3-diamine (Intermediate 162, 333 mg, 0.73 mmol) in CH _{2 Cl2}

- 40 046985 (6 ml), which was cooled in an ice/CH3OH bath. The mixture was then stirred for 0.5 h, then diluted with 10% CH3OH in CH2Cl2. The resulting solution was washed with sat. NaHCO ₃ , dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 1-10% methanolic ammonia in CH2Cl2 and trituration with diethyl ether gave the title compound (193 mg, 52%) as a beige solid.

^1H NMR: 1.69 (2H, dt), 2.03-2.08 (2H, m), 2.38 (3H, s), 2.63 (2H, t), 3.65 (2H, d), 3.83 (3H, s), 3.94 ( 2Н, d), 5.68 (1H, dd), 6.19 (1H, dd), 6.25 (1H, s), 6.47 (1H, dd), 7.06 (1H, td), 7.19 (1H, d), 7.44 (1H , dd), 7.67 (1H, s), 7.98 (1H, s), 8.29 (1H, d), 8.47 (1H, d), 8.75 (1H, s), 8.78 (1H, d), 9.25 (1H, s); m/z: ES+MH+ 511.34.

Example 57 -2-enamid.

A solution of acryloyl chloride (0.604 ml, 1 M in CH2Cl2, 0.60 mmol) was added dropwise to 4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-N-[4-(1H-indol-3-yl )pyrimidin-2-yl]-6-methoxybenzene-1,3diamine (Intermediate 164, 268 mg, 0.60 mmol) in CH ₂ Cl ₂ (10 ml) and 10 ml DMA, which was cooled to -5°C. The resulting mixture was stirred at -5°C for 1 hour and then diluted with CH ₂ Cl ₂ (100 ml). The resulting solution was washed with sat. NaHCO3 (25 ml), water (25 ml) and then sat. brine (4x25 ml) and then concentrated in vacuo. Purification by FCC eluting with 0-30% CH ₃ OH in CH ₂ Cl ₂ gave the title compound (135 mg, 45%) as a beige solid.

¹ NMR (CDCl3) 1.98 (1H, s), 2.18 (1H, d), 2.94 (1H, s), 3.11 (4H, d), 3.88 (3H, s), 5.73 (1H, d), 6.40 (2H , d), 6.76 (1H, s), 7.17 (1H, d), 7.22-7.24 (1H, m), 7.41-7.46 (1H, m), 7.62 (1H, s), 8.16 (1H, s), 8.39 (1H, d), 8.45 (1H, s), 8.75 (1H, s), 8.86 (1H, s), 9.56 (1H, s); m/z: ES+ MH+ 498.

Example 58. No. (2-[3-Dimethylaminoazetidin-1-yl]-5-{[4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-4methoxyphenyl)prop-2-enamide.

A solution of acryloyl chloride (0.522 ml, 1 M in CH ₂ Cl ₂ , 0.52 mmol) was added dropwise to 4-(3dimethylaminoazetidin-1-yl)-N-[4-(1H-indol-3-yl)pyrimidin-2 -yl]-6-methoxy-benzene-1,3-diamine (Intermediate 166, 224 mg, 0.52 mmol) in CH2Cl2 (10 ml) and the mixture was then stirred at 5°C for 1 hour. The mixture was then diluted CH2Cl2 (100 ml) and the resulting solution was washed with sat. NaHCO3 (25 ml), water (25 ml) and then sat. brine (25 ml) and then concentrated in vacuo. Purification by FCC eluting with 0-30% CH3OH in CH2Cl2 gave the title compound (46 mg, 18%) as a beige solid.

1H NMR: 2.09 (6H, d), 3.09 (1H, s), 3.56 (2H, t), 3.85 (3H, s), 3.96 (2H, t), 5.68 (1H, dd), 6.20 (1H, dd ), 6.26 (1H, s), 6.50 (1H, dd), 7.14 (2H, dt), 7.18 (1H, t), 7.40-7.46 (1H, m), 7.82 (1H, s), 7.90 (1H, s), 8.23 (1H, d), 8.31 (1H, d), 8.38 (1H, d), 9.34 (1H, s), 11.76 (1H, s); m/z: ES+ MH+ 484.

Example 5 9. No. (2-[2-Dimethylaminoethyl-methylamino]-5 -{[4-(1 H-indol-3-yl)pyrimidin-2yl]amino } -4-methoxyphenyl)prop-2-enamide

A solution of acryloyl chloride (0.584 ml, 1 M in CH2Cl2, 0.58 mmol) was added dropwise to N-(2-dimethylaminoethyl)-M ⁴ -[4-(1H-indol-3-yl)pyrimidin-2-yl]- 5-methoxy-M1-methylbenzene-1,2,4triamine (Intermediate 168, 252 mg, 0.58 mmol) in CH2Cl2 (10 ml) and the mixture was then stirred at -5°C for 1 hour. The mixture was then diluted with CH2Cl2 (100 ml) and the resulting solution was washed with sat. NaHCO3 (25 ml), water (25 ml) and then sat. brine (25 ml) and then concentrated in vacuo. Purification by FCC eluting with 0-30% CH3OH in CH2Cl2 gave the title compound (76 mg, 27%) as a white solid.

1H NMR (CDCl) ₃ 2.25 (6H, s), 2.27-2.34 (3H, m), 2.69 (3H, s), 2.84-2.94 (2H, m), 3.87 (3H, s), 5.68 (1H, dd ), 6.40 (1H, d), 6.48 (1H, dd), 6.78 (1H, s), 7.03 (1H, d), 7.08-7.20 (2H, m), 7.33 (1H, dd), 7.65 (1H, s), 8.12 (1H, d), 8.26 (1H, d), 8.59 (1H, s), 9.74 (1H, s), 9.97 (1H, s), 10.24 (1H, s); m/z: ES+ MH+ 486.

- 41 046985

Example 60 2-enamide

A solution of tert-butylA-[2-[[5-methoxy-4-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]-2-(prop-2enoylamino)phenyl]-methylamino] ethyl]A-methylcarbamate (Intermediate 170, 321 mg, 0.55 mmol) in CH ₂ Cl ₂ (10 ml) and TFA (2 ml) were stirred at RT. for 0.5 h and then concentrated in vacuo. The residue was dissolved in 10% CH ₃ OH/CH ₂ Cl ₂ . The resulting solution was washed with sat. NaHCO ₃ , dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 0-20% CH3OH in CH ₂ Cl ₂ and trituration with diethyl ether provided the title compound (110 mg, 41%) as a pale yellow solid.

1H NMR: 2.35 (3H, s), 2.58-2.62 (2H, m), 2.71 (3H, s), 2.85-2.89 (2H, m), 3.86 (3H, s), 3.92 (3H, s), 5.74 (1H, dd), 6.28 (1H, dd), 6.59 (1H, dd), 6.99 (1H, s), 7.15 (1H, t), 7.21-7.27 (2H, m), 7.53 (1H, d), 7.87 (1H, s), 8.24 (1H, d), 8.32 (1H, d), 8.66 (1H, s), 9.16 (1H, s), 10.33 (1H, s); m/z: ES+ MH+ 486.55.

Intermediate 1. 4-Methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N'-(5-methyl-4pyrazolo[1,5-a]pyridin-3- ilpyrimidin-2-yl)benzene-1,3-diamine.

A mixture of N-[2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitrophenyl]-5-methyl-4-pyrazolo[1,5-a]pyridine -3-ylpyrimidin-2-amine (Intermediate 2, 279 mg, 0.59 mmol), iron (198 mg, 3.55 mmol) and NH4Cl (22.16 mg, 0.41 mmol) in ethanol (10, 5 ml) and water (3.50 ml) were refluxed for 0.75 h. Then additional NH ₄ Cl (22.16 mg, 0.41 mmol) and iron (198 mg, 3.55 mmol) were added ) and the mixture was refluxed for an additional 1.5 hours. The mixture was then cooled, filtered and the filtrate was concentrated in vacuo. As a result of purification by FCC eluting with 2-10% 7N. methanolic ammonia in CH ₂ Cl ₂ and trituration with THF and washing the resulting solid with diethyl ether gave the title compound (150 mg, 57%) as a beige crystalline solid.

1H NMR: 2.30 (3H, s), 2.40 (5H, m), 2.59 (2H, t), 3.01 (2H, d), 3.73 (3H, s), 4.27 (2H, s), 5.71 (1H, s ), 6.63 (1H, s), 7.10 (1H, m), 7.35-7.49 (2H, m), 7.83 (1H, s), 8.27 (1H, s), 8.50-8.63 (2H, m), 8.81 ( 1H, d); m/z: ES+ MH+ 442.

Intermediate 2. N-[2-Methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitrophenyl]-5-methyl-4-pyrazolo[1,5- a]pyridin-3-ylpyrimidin-2-amine.

Solution of 3-(2-chloro-5-methylpyrimidin-4-yl)pyrazolo[1,5-a]pyridine (Intermediate 5, 271 mg, 1.00 mmol), p-toluenesulfonic acid monohydrate (271 mg, 1.00 mmol) 43 mmol) and 2-methoxy-4(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitroaniline (Intermediate 3, 250 mg, 0.95 mmol) were refluxed at 2-pentanol (12 ml) under N2 for 30 hours. The mixture was then concentrated in vacuo and the residue was dissolved in CH3OH. Purification by ion exchange chromatography (SCX column) eluting with 7 M methanol ammonia and trituration with CH3CN gave the title compound (283 mg, 63%) as an orange powder.

1H NMR: 2.28-2.36 (5H, m), 2.44 (3H, s), 2.60 (2H, t), 3.00 (2H, d), 4.00 (3H, d), 5.64 (1H, s), 6.97 (1H , s), 7.13 (1H, m), 7.40 (1H, m), 8.27 (1H, s), 8.39 (1H, s), 8.53 (1H, d), 8.61 (1H, s), 8.83 (1H, d), 8.87 (1H, s); m/z: ES ^- MH ^- 470.

Intermediate 3: 2-Methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitroaniline.

Mixture of 4-bromo-2-methoxy-5-nitroaniline (Intermediate 4, 1.112 g, 4.5 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-3,6-dihydro-2H-pyridine (1.004 g, 4.50 mmol) and K ₂ CO ₃ (2.488 g, 18.00 mmol) were stirred in 1,4-dioxane (20 ml) and water (5 ml). The mixture was purged with N2 for 0.25 hours. Tetrakis(triphenylphosphine)palladium(0) (0.052 g, 0.05 mmol) was then added and the mixture was refluxed for 2 hours. The mixture was then cooled, filtered and the filtrate was concentrated in vacuum to obtain an aqueous mixture. This mixture was dissolved in EtOAc and water and the phases were separated. The aqueous solution was extracted with EtOAc. The combined organic solutions were then extracted twice with 2 M HCl (40 ml). Aqueous solutions were made alkaline with 2 M Na2CO3 (50 ml) and extracted with EtOAc (3x40 ml). The combined organic solutions were dried (MgSO ₄ ) and concentrated in vacuo. The residue was dissolved in a mixture of CH ₂ Cl ₂ and 2N. methanolic ammonia (10:1, 10 ml) and the solution was filtered through a pad of silica. The filtrate was concentrated in vacuo to give an oil, which then crystallized. After trituration with isohexane and diethyl ether (1:1, 5 ml) and collection,

- 42046985 of the solid was obtained by filtration to obtain the title compound (1.093 g, 92%) as a yellow crystalline solid.

1H NMR: 2.23 (2H, dd), 2.27 (3H, s), 2.53 (2H, t), 2.93 (2H, d), 3.87 (3H, s), 5.27 (2H, s), 5.42-5.53 (1H , m), 6.65 (1H, s), 7.23 (1H, s); m/z: ES ⁺ MH ⁺ 264.

Intermediate 4: 4-Bromo-2-methoxy-5-nitroaniline.

85% sulfuric acid was prepared by carefully adding 98% sulfuric acid (13 ml) to ice (2 g). Guanidine nitrate (1.221 g, 10.00 mmol) was added in portions over a period of 10 min to a cooled (0-5°C) mixture of 4-bromo-2-methoxyaniline (2.020 g, 10 mmol) in 85% sulfuric acid (15.68 ml, 250.00 mmol). The resulting dark blue mixture was stirred at 0-5°C for 0.75 hours and then poured very slowly into a well-stirred mixture of 50% aq. NaOH (40 ml) and ice (120 g). The orange precipitate was collected by filtration, washed with water (4x50 ml) and air dried. This material was dissolved in diethyl ether (100 ml) and filtered through a silica pad. The resulting solution was diluted with isohexane and purified by evaporation crystallization from diethyl ether/isohexane to give the title compound (1.821 g, 74%) as an orange crystalline solid.

^1H NMR: 3.90 (3H, s), 5.52 (2H, s), 7.14 (1H, s), 7.32 (1H, s).

Intermediate 5: 3-(2-Chloro-5-methylpyrimidin-4-yl)pyrazolo[1,5-a]pyridine.

K ₂ CO ₃ (10.60 g, 76.68 mmol) at RT. was added to a mixture of 4-[(E)-2-butoxyethenyl]-2-chloro-5methylpyrimidine (Intermediate 6, 6.95 g, 30.67 mmol) and 1-aminopyridinium iodide (9.19 g, 41.40 mmol ) in DMF (40 ml). The resulting dark blue suspension was stirred at room temperature. for 3 days (it turned a deep red color) and then heated at 110°C for 3 hours. The mixture was then cooled, diluted with EtOAc (100 ml) plus a small amount of CH ₂ Cl ₂ . This solution was washed with water (100 ml) and the aqueous solution was extracted with EtOAc (100 ml). The combined organic solutions were washed with water (4x100 ml) and sat. brine (50 ml), dried (MgSO ₄ ) and concentrated in vacuo. The residue was dissolved in THF (100 ml) and filtered through a pad of 30 g of silica. The eluted solution was concentrated in vacuo and the residue was washed with CH3OH at -70°C to give the title compound (2.223 g, 30%) as a beige crystalline solid.

1H NMR: 2.53 (3H, s), 7.22 (1H, m), 7.64 (1H, m), 8.53-8.59 (2H, m), 8.70 (1H, s), 8.90 (1H, d); m/z: ES ⁺ MH ⁺ 245.

Intermediate 6: 4-[(E)-2-Butoxyethenyl]-2-chloro-5-methylpyrimidine.

Diacetoxypalladium (0.482 g, 2.15 mmol) under N2 was added in one portion to a mixture of 1-(vinyloxy)butane (11.91 ml, 92.02 mmol), 2,4-dichloro-5-methylpyrimidine (5 g, 30. 67 mmol) and triethylamine (4.51 ml, 32.21 mmol) in degassed polyethylene glycol 200 (25 ml). The resulting mixture was stirred at 80°C for 18 hours. The mixture was then cooled and extracted with diethyl ether (3x75 ml). The combined organic solutions were dried (MgSO ₄ ), diluted with heptane (115 ml) and filtered through a pad of 75 g of silica eluting with 2:1 diethyl ether/heptanes to give the title compound (8.62 g, 124%) as yellow oil, which was used without further purification.

1H NMR: 0.92 (3H, t), 1.35-1.43 (2H, m), 1.60-1.71 (2H, m), 2.17 (3H, d), 4.06 (2H, t), 5.93 (1H, d), 7.90 (1H, d), 8.33 (1H, d); m/z: ES ⁺ MH ⁺ 226.

Intermediate 7. N-[5-Chloro-4-(III-indol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(1methyl-3,6-dihydro-2H-pyridin-4 - yl)benzene-1,3-diamine.

NaOH (2 M, 1.488 ml, 2.98 mmol) at r.t. under N2 was added in one portion to the mixture N'-{4-[1-(benzenesulfonyl)indol-3-yl]-5-chloropyrimidin-2-yl}-4-methoxy-6-(1-methyl-3,6- Dihydro-2Hpyridin-4-yl)benzene-1,3-diamine (Intermediate 8, 283 mg, 0.47 mmol) in CH ₃ OH (6 ml). The resulting solution was stirred at reflux for 0.5 hours. Dry ice was then added and the resulting mixture was concentrated in vacuo. The resulting residue was triturated with CH2Cl2/CH3OH (4:1, 20 ml), filtered and the filtrate was concentrated in vacuo to give a residue. Purification by FCC eluting with 2-10% methanol ammonia in CH ₂ Cl ₂ provided the title compound (102 mg, 47%) as a pale yellow powder.

1H NMR: 2.30 (3H, s), 2.41 (2H, s), 2.60 (2H, t), 3.02 (2H, d), 3.70 (3H, s), 4.27 (2H, s), 5.73 (1H, s ), 6.65 (1H, s), 7.08 (1H, t), 7.17-7.23 (1H, m), 7.26 (1H, s), 7.48 (1H, d), 8.18 (1H, s), 8.38 (1H, s), 8.41 (1H, d), 8.49 (1H, s), 11.85 (1H, s); m/z: ES ⁺ MH ⁺ 460.

Intermediate 8. No-{4-[1-(Benzenesulfonyl)indol-3-yl]-5-chloropyrimidin-2-yl}-4methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin- 4-yl)benzene-1,3-diamine.

Mixture of 4-[1-(benzenesulfonyl)indol-3-yl]-5-chloro-N-[2-methoxy-4-(1-methyl-3,6-dihydro-2Hpyridin-4-yl)-5-nitrophenyl ]pyrimidin-2-amine (Intermediate 9, 349 mg, 0.47 mmol), iron (157 mg, 2.82 mmol) and NH4Cl (17.60 mg, 0.33 mmol) in ethanol (9 ml) and water (3 ml) was refluxed for 1.5 hours. The mixture was cooled and concentrated in vacuo. CH2Cl2 (20 ml) and CH3OH (2 ml) were then added and the mixture was stirred for 5 min and then filtered. Organic

- 43 046985 The solution was washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the title compound (396 mg, 140%) as a green foam, which was used without further purification, m/z: ES ⁺ MH ⁺ 601 .

Intermediate 9. 4-[1-(Benzenesulfonyl)indol-3-yl]-5-chloro-N-[2-methoxy-4-(1methyl-3,6-dihydro-2H-pyridin-4-yl)- 5-nitrophenyl]pyrimidin-2-amine.

A mixture of 1-(benzenesulfonyl)-3-(2,5-dichloropyrimidin-4-yl)indole (Intermediate 10, 384 mg, 0.95 mmol), p-toluenesulfonic acid monohydrate (271 mg, 1.43 mmol) and 2-methoxy-4-(1methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitroaniline (Intermediate 3, 250 mg, 0.95 mmol) was refluxed in 2-pentanol (12 ml) under N ₂ for 24 hours. Additional p-toluenesulfonic acid monohydrate (0.090 g, 0.48 mmol) was then added and the mixture was refluxed for an additional 6 hours. The mixture was then concentrated in vacuo and the resulting residue was dissolved in mixtures of CH ₂ Cl ₂ , CH ₃ OH and EtOAc (10, 3 and 3 ml). This solution was concentrated in vacuo on silica. Purification by FCC eluting with 4-10% CH3OH in CH ₂ Cl ₂ gave the title compound (415 mg, 56%) as a yellow foam.

¹ H NMR: 2.29 (1.95H, s), 2.52 (0.7H, m), 2.73 (2.6H, s), 3.18 (1.4H, m), 3.57 (2H, s), 3.96 (3H, s), 5.68 (1H, s), 7.00 (1H, s), 7.11 (1.3H, d), 7.26 (1H, m), 7.44 (1H, m), 7.49 (1.3H, d), 7.64 (2H, t) , 7.73 (1H, m), 8.01 (1H, d), 8.07-8.15 (2H, m), 8.19 (1H, d), 8.64 (2H, d), 8.70 (1H, s), 8.97 (1H, s ); (the spectrum appears to show a mixture of rotamers, which results from the limited rotation of bonds within the molecule) m/z: ES ⁺ MH ⁺ 631.

Intermediate 10: 1-(Benzenesulfonyl)-3-(2,5-dichloropyrimidin-4-yl)indole.

Sodium tert-Butoxide (529 mg, 5.50 mmol) at r.t. under N2 was added in portions over a period of 2 min to a mixture of 3-(2,5-dichloro-pyrimidin-4-yl)-N-indole (Intermediate 11, 1.321 g, 5.0 mmol) and benzenesulfonyl chloride (0.645 ml, 5.00 mmol) in DMF (30 ml). The resulting solution was stirred at room temperature. for 1 hour. Additional benzenesulfonyl chloride (0.064 ml, 0.50 mmol) and sodium tert-butoxide (0.053 g, 0.055 mmol) were added and the mixture was stirred at room temperature. for an additional 0.25 hours. The reaction was quenched by the addition of CH ₃ OH (6 ml) and neutralized by the addition of solid CO ₂ pellets until a pH value of 7 was reached. The solvent was then removed in vacuo and the resulting residue was dissolved in CH ₂ Cl ₂ ( 100 ml). This solution was filtered through a pad of 20 g of silica and eluted with a solution of dilute isohexane (50 ml). This solution was concentrated in vacuo to a volume of 70 ml and then cooled. The resulting crystalline precipitate was collected by filtration, washed with isohexane/CH ₂ Cl ₂ (4:1, 50 ml) and dried by aspiration to obtain the title compound (923 mg, 46%) as an off-white crystalline solid, which was used without further purification.

1H NMR: 7.39-7.53 (2H, m), 7.64 (2H, t), 7.75 (1H, t), 8.04 (1H, d), 8.11-8.17 (2H, m), 8.28 (1H, d), 8.79 (1H, s), 9.00 (1H, s); m/z: ES+MH+ 404.

Intermediate 11. 3-(2,5-Dichloropyrimidin-4-yl)-III-indole CH ₃ MgBr (3.2 M in 2-methyltetrahydrofuran, 3.37 ml, 10.79 mmol) was added at 0° C. drops over 10 min to a solution of indole (1.28 g, 10.79 mmol) in THF (6 ml). The solution was then stirred at 0-2°C for 0.5 h. 2,4,5-trichloropyrimidine (1 g, 5.40 mmol) was then added dropwise to give a yellow solution. The ice bath was removed, then the solution was stirred at room temperature. for 1 hour, obtaining a red solution. The mixture was heated to 60°C and then stirred at 60°C for 1.5 hours. The mixture was then cooled to room temperature. and acetic acid (634 μL, 11.06 mmol) was added dropwise. Water (9.90 ml) and THF (2 ml) were added, then the mixture was stirred for 20 minutes at 60°C, obtaining a two-phase solution. The layers were separated and heptane (11 ml) was added to the organic solution, resulting in crystallization of the solid. The solid was collected by filtration, washed with heptane (2 mL) and dried in a vacuum oven to give the title compound (1.015 g, 66%) as a yellow solid.

1H NMR: 7.24-7.32 (2H, m), 7.55-7.58 (1H, m), 8.52-8.55 (1H, m), 8.71-8.73 (2H, m), 12.24 (1H, s); m/z: ES ⁺ MH ⁺ 264, 266.

Intermediate 12. N-[4-(III-Indol-3-yl)-5-methylpyrimidin-2-yl]-4-methoxy-6-(4methylpiperazin-1-yl)benzene-1,3-diamine.

A mixture of 4-(III-indol-3-yl)-H-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-5-methylpyrimidin-2-amine (Intermediate 13, 157 mg, 0.33 mmol), iron (111 mg, 1.99 mmol) and NH4Cl (12.41 mg, 0.23 mmol) were refluxed in ethanol (6 ml) and water (2 ml) for 2 h. The mixture was then cooled and concentrated in vacuo to obtain a thick suspension. CH2Cl2 (100 ml) and CH3OH (10 ml) were then added and the mixture was stirred for 0.25 h, then filtered. The filter cake was washed with CH ₂ Cl ₂ (50 ml) and CH3OH (5 ml) and the combined organic solutions were dried (MgSO4) and concentrated in vacuo. Purification by FCC eluting with 1-5% methanolic ammonia in CH ₂ Cl ₂ provided the title compound (113 mg, 77%) as a pale yellow dry film; m/z: ES ⁺ MH ⁺ 444.53.

Intermediate 13. 4-(III-Indol-3-yl)-H-[2-methoxy-4-(4-methylpiperazin-1-yl)-5

- 44 046985 nitrophenyl]-5-methylpyrimidin-2-amine.

A mixture of 2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitroaniline (Intermediate 14, 204 mg, 0.77 mmol), p-toluenesulfonic acid monohydrate (291 mg, 1.53 mmol) and 3 -(2-chloro-5methylpyrimidin-4-yl)-III-ivdol (Intermediate 17, 192 mg, 0.77 mmol) was heated at 120°C in 2-pentanol (15 ml) for 24 h, giving dark brown suspension. The mixture was then concentrated in vacuo and the resulting residue was dissolved in a mixture of CH ₂ Cl ₂ and CH ₃ OH (50 ml and 5 ml) and this solution was concentrated on silica in vacuo. Purification by FCC eluting with 1-5% methanol ammonia in CH ₂ Cl ₂ gave the title compound (157 mg, 43%) as an orange gum; m/z: ES ⁺ MH ⁺ 474.24.

Intermediate 14: 2-Methoxy-4-(4-methylpiperazin-1-yl)-5-nitroaniline.

tert-Butyl-H-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]carbamate (Intermediate 15, 1.4 g, 3.82 mmol) was dissolved in CH ₂ Cl ₂ ( 20 ml) and then TFA (5 ml) was added. The mixture was stirred for 2 hours at room temperature. and then concentrated in vacuo. The resulting residue was dissolved in CH3OH, absorbed onto an SCX column, washed with CH3OH and eluted with methanolic ammonia. The fractions that contained the product were combined and concentrated. As a result of purification by FCC eluting with 1.5% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (0.6 g, 59%) as an orange oil which crystallized on standing.

1H NMR: 2.22 (3H, s), 2.39-2.47 (4H, m), 2.87-2.97 (4H, m), 3.88 (3H, s), 4.99 (2H, s), 6.72 (1H, s), 7.20 (1H, s); m/z: ES ⁺ MH ⁺ 267.5.

Intermediate 15. tert-Butyl-N-[2-methoxy-4-(4-methylpiperazin-1-yl)-5nitrophenyl]carbamate.

2-Methoxy-4-(4-methylpiperazin-1-yl)-5-nitrobenzoic acid (Intermediate 16, 1.5 g, 5.08 mmol) was suspended in a mixture of tert-butanol (20 ml) and DIPEA (1.318 ml , 7.62 mmol) and then diphenylphosphoryl azide (1.642 ml, 7.62 mmol) was added. The mixture was then refluxed for 2 hours. The mixture was then cooled and concentrated in vacuo. The resulting residue was dissolved in EtOAc, washed with sat. NaHCO ₃ , dried (Na ₂ SO ₄ ) and concentrated in vacuo. As a result of purification by FCC eluting with 2% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (1.45 g, 78%) as an orange oil which crystallized on standing.

1H NMR: 1.45 (9H, s), 2.23 (3H, s), 2.41-2.49 (4H, m), 2.99-3.07 (4H, m), 3.92 (3H, s), 6.74 (1H, s), 8.248 .32 (2Н, m); m/z: ES ⁺ MH ⁺ 367.3.

Intermediate 16: 2-Methoxy-4-(4-methylpiperazin-1-yl)-5-nitrobenzoic acid.

1-Methylpiperazine (0.962 ml, 8.67 mmol) was added to a suspension of 2-methoxy-4,5-dinitrobenzoic acid (2.0 g, 8.26 mmol) in water (5 ml). The mixture was heated at 50°C for 1.5 hours, then at 75°C for 3 hours. An additional 0.5 eq. 1-methylpiperazine and the mixture was heated overnight. The mixture was then left to cool and stand. A crystalline solid formed which was collected by filtration, washed with water and then filter dried to give the title compound (1.87 g, 77%) as a yellow crystalline solid.

1H NMR: 2.25 (3H, s), 2.45-2.49 (4H, m), 3.13-3.21 (4H, m), 3.93 (3H, s), 6.63 (1H, s), 8.32 (1H, s); m/z: ES ⁺ MH ⁺ 296.5.

Intermediate 17. 3-(2-Chloro-5-methylpyrimidin-4-yl)-III-indole.

CH ₃ MgBr (3.2 M in 2-methyltetrahydrofuran, 3.76 ml, 12.02 mmol) at 0°C was added dropwise over 10 min to a solution of indole (1.42 g, 12.02 mmol) in THF (4.9 ml). The solution was then stirred at 0-2°C for 0.5 h. A solution of 2,4-dichloro-5-methylpyrimidine (1 g, 6.01 mmol) in THF (3 ml) was then added dropwise to the solution. The ice bath was then removed, then the solution was stirred at room temperature. for 1 hour, then at 60°C for 21 hours. Still at 60°C, acetic acid (708 μl, 12.32 mmol) was added dropwise, then water (10 ml). The resulting two-phase suspension was stirred at 60°C for 0.5 h. The resulting solid was collected by filtration, washed with water (5 ml) and dried in a vacuum oven to obtain the title compound (805 mg, 50%) as a white solid .

1H NMR: 2.49 (3H, s), 7.20-7.28 (2H, m), 7.52-7.55 (1H, m), 8.20 (1H, d), 8.48 (1H, d), 8.51-8.54 (1H, m) , 12.10 (1H, s); m/z: ES ⁺ MH ⁺ 244.

Intermediate 18. K-(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-[(3K)3-dimethylaminopyrrolidin-1-yl]-6-methoxybenzene -1,3 -diamine

Mixture of 5-chloro-N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitro-phenyl}-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidine -2-amine (Intermediate 19, 145 mg, 0.28 mmol), iron (95 mg, 1.71 mmol) and NH4Cl (11.4 mg, 0.21 mmol) were refluxed in ethanol (6 ml ) and water (2 ml) for 1.5 hours. The mixture was then cooled and concentrated in vacuo. The resulting residue was triturated for 15 min using 10% CH3OH in CH2Cl2 (15 ml) and the mixture was then filtered. The residue was triturated again using 10% CH3OH in CH2Cl2 (15 ml) and the mixture was filtered. The combined filtrates were washed with brine, dried (Na2SO4) and concentrated in vacuo. As a result of purification by FCC eluting with 2% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (112 mg, 82%) as a yellow gum.

- 45 046985 ¹ H NMR (CDCI3): 1.83-1.96 (1H, m), 2.08-2.23 (1H, m), 2.30 (6H, s), 2.82-2.92 (1H, m), 2.99-3.13 (2H, m), 3.17-3.28 (2H, m), 3.65 (2H, s), 3.84 (3H, s), 6.72 (1H, s), 6.96 (1H, td), 7.38 (1H, ddd), 7.52 (1H , s), 7.90 (1H, s), 8.36 (1H, s), 8.55-8.60 (1H, m), 8.65 (1H, dd), 8.94 (1H, s); m/z: ES ⁺ MH ⁺ 479.5.

Intermediate 19. 5-Chloro-N-[4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin- 2-am.

(3R)-N,N-Dimethylpyrrolidin-3-amine dihydrochloride (90 mg, 0.48 mmol) was added to a suspension of 5-chloro-H-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[ 1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 20, 200 mg, 0.48 mmol) and DIPEA (0.250 ml, 1.45 mmol) in DMA (3 ml). This mixture was heated at 140° C. under microwave conditions for 0.5 h. The mixture was then diluted with CH ₃ OH and absorbed onto an SCX column, washed with CH ₃ OH and eluted with 1:1 methanol ammonia in CH ₂ Cl ₂ . Fractions containing product were combined and concentrated in vacuo. As a result of purification by FCC eluting with 1.5% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (149 mg, 61%) as an orange foam.

1H NMR: 1.76-1.89 (1H, m), 2.14-2.25 (7H, m), 2.69-2.84 (1H, m), 3.12-3.27 (3H, m), 3.41-3.53 (1H, m), 3.89 ( 3H, s), 6.56 (1H, s), 7.13 (1H, td), 7.26-7.38 (1H, m), 8.06 (1H, s), 8.40-8.43 (2H, m), 8.73 (1H, s) , 8.85 (1H, d), 8.95 (1H, s); m/z: ES ⁺ MH ⁺ 509.5.

Intermediate 20: 5-Chloro-H-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5a]pyridin-3-ylpyrimidin-2-amine.

Mixture of 3-(2,5-dichloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine (Intermediate 21, 1.4 g, 5.28 mmol), 4-fluoro-2-methoxy-5-nitroaniline (Intermediate 23, 1.032 g, 5.55 mmol) and p-toluenesulfonic acid monohydrate (1.105 g, 5.81 mmol) were heated at 125°C in 2-pentanol (40 ml) for 18 hours. The mixture was then cooled and the solid was collected by filtration. The solid was washed with CH3OH and diethyl ether and then filter dried to give the title compound (1.73 g, 79%) as a yellow powder.

1H NMR: 3.98 (3H, s), 7.16 (1H, td), 7.33-7.48 (2H, m), 8.49 (1H, d), 8.53 (1H, d), 8.66 (1H, d), 8.86 (1H , d), 8.90 (1H, s), 8.96 (1H, s).

Intermediate 21: 3-(2,5-Dichloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine.

K ₂ CO ₃ (20.82 g, 150.65 mmol) and KOH (16.91 g, 301.31 mmol) at RT. added in one portion to a mixture of (E)-4-(2-butoxyvinyl)-2,5-dichloropyrimidine (Intermediate 22, 74.46 g, 301.31 mmol) and 1-aminopyridinium iodide (66.9 g, 301. 31 mmol) in DMSO (1.415 L). The mixture was stirred at room temperature. for 1.5 h and then at 90°C for 4 h. After cooling, the mixture was diluted with water (5 L) and stirred for 0.5 h. The resulting solid was collected by filtration and washed with water (5 L). Purification by FCC eluting with 0-20% EtOAc in CH ₂ Cl ₂ and trituration with diethyl ether gave the title compound (16.2 g, 20%) as a cream solid.

1H NMR: 7.29 (1H, td), 7.74 (1H, ddd), 8.58 (1H, dt), 8.82 (1H, s), 8.98 (1H, dt), 9.10 (1H, s). m/z: ES ⁺ , MH ⁺ 264.89.

Intermediate 22: 4-[(E)-2-Butoxyethenyl]-2,5-dichloropyrimidine.

Degassed 1,4-dioxane (600 mL) under N2 was added to palladium(P) acetate (4.80 g, 21.37 mmol). n-Butyl vinyl ether (275 ml, 2.137 mol), 2,4,5-trichloropyrimidine (200 g, 1.069 mol) and DIPEA (194 ml, 1.122 mol) were then added. The mixture was heated to 80°C for 22.5 hours and then cooled to 30°C. Palladium acetate (2.40 g, 10.68 mmol), n-butyl vinyl ether (138 ml, 1.068 mol) and DIPEA (97 ml, 561 mmol) were then added. The mixture was then heated to 80°C for 4 hours and then left to cool to room temperature. during the night. The mixture was then added to water (2 L) and then saturated. brine (2 l). The phases were separated and the aqueous solution was extracted with methyl tert-butyl ether (2x1 L). The combined organic solutions were washed with water to obtain an emulsion, which was not separated. The whole thing was filtered and the two phases were then separated. The organic solution was dried (MgSO ₄ ) and concentrated to give a brown oil (240 g). This material was divided into two batches and each was purified by FCC eluting with 0-100% heptane in CH2Cl2 to give the title compound (130 g, 49%) as a yellow oil.

1H NMR: 0.89-0.97 (3H, t), 1.33-1.45 (2H, m), 1.62-1.72 (2H, m), 4.13 (2H, t), 6.08 (1H, d), 8.06 (1H, d) , 8.64 (1H, s); m/z: ES ⁺ MH ⁺ 247.41.

Intermediate 23: 4-Fluoro-2-methoxy-5-nitroaniline.

4-Fluoro-2-methoxyaniline (2.4 g, 17.00 mmol) was added in portions to concentrated H ₂ SO ₄ (15 ml), which was cooled in an ice/water bath, where the temperature was kept below 15°C during the addition. The mixture was stirred until any solid that had formed was dissolved. KNO3 (0.815 mL, 17.00 mmol) was added in portions so that the temperature was maintained below 10°C. The mixture was stirred overnight and then poured into the ice/water mixture. The mixture was made alkaline with concentrated NH4OH. The resulting solid was filtered and then dissolved in CH2Cl2, washed with water, dried (Na ₂ SO ₄ ) and concentrated on silica. Purification by FCC eluting with 50-0% heptane in CH ₂ Cl ₂ provided the title compound (2.450 g, 77%) as a yellow crystalline solid.

- 46 046985 ¹ H NMR: 3.91 (3H, s), 5.21 (2H, s), 7.03 (1H, d), 7.35 (1H, d); m/z: ES ⁺ MH ⁺ 187.4.

Intermediate 24. H-(5-H.tor-4-pyrazo.to[1,5-a|pyridin-3-ylpyrimidin-2-yl)-4-(3dimethylaminoazetidin-1-yl)-6-methoxybenzene- 1,3-diamine

A mixture of 5-chloro-X-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitro(|)enyl|-4-pyrazolo[1.5a]pyridin-3-ylpyrimidin-2-amine ( Intermediate 25, 265 mg, 0.54 mmol), iron (179 mg, 3.21 mmol) and NH ₄ Cl (20.05 mg, 0.37 mmol) were refluxed in ethanol (6 ml) and water (2 ml) for 1 hour. The crude product was purified by ion exchange chromatography using an SCX column. The title product was eluted from the column using 7 M methanolic ammonia and the appropriate fractions were concentrated in vacuo to give the title compound (235 mg, 94%) as a yellow solid which was used without further purification.

1H NMR: 2.13 (6H, s), 3.07 (1H, s), 3.50 (2H, t), 3.66 (3H, s), 4.00 (3H, t), 4.05 (2H, s), 6.28 (1H, s ), 6.79 (1H, s), 7.10 (1H, t), 7.3-7.39 (1H, m), 8.33 (1H, s), 8.37 (1H, s), 8.80 (1H, d), 8.93 (1H, s); m/z: ES ⁺ MH ⁺ 465.25.

Intermediate 25. 5-Chloro-Io[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5nitrophenyl|-4-pyrazolo[1,5-a|pyridin-3-ylpyrimidin-2-amine.

DIPEA (0.341 ml, 1.96 mmol) was added to a mixture of 5-chloro-Yo(4-fluoro-2-methoxy-5-nitrophenyl)-4(pyrazolo[1,5-a|pyridin-3-yl)pyrimidin- 2-amine (Intermediate 20, 254 mg, 0.61 mmol) and Yudimethylazetidin-3-amine dihydrochloride (Intermediate 26, 106 mg, 0.61 mmol) in DMA (4 ml) and the mixture was heated to 100°C in for 0.5 h. Additional N-I-dimethylazetidine-3-amine (35 mg, 0.19 mmol) was then added and the mixture was heated at 100°C for an additional 2 h and then left at room temperature. during the night. The mixture was purified directly by ion exchange chromatography using an SCX column. The target product was eluted from the column using 7 M methanolic ammonia and concentrated in vacuo on silica. As a result of purification by FCC eluting with 0-4% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (310 mg, 102%) as an orange solid which was used without further purification.

1H NMR: 2.14 (6H, s), 3.08-3.18 (1H, m), 3.76 (2H, dd), 3.89 (3H, s), 4.02-4.11 (2H, m), 6.28 (1H, s), 7.12 (1H, td), 7.30-7.39 (1H, m), 8.12 (1H, s), 8.37 (1H, br s), 8.42 (1H, s), 8.68 (1H, s), 8.83 (1H, d) , 8.94 (1H, d); m/z: ES ⁺ MH ⁺ 495.56.

Intermediate 26. Judimethylazetidine-3-amine hydrochloride salt.

HCl in diethyl ether (200 ml) was added slowly to a solution of tert-butyl-3-dimethylaminoazetidine-1-carboxylate (Intermediate 27, 62 g, 0.31 mol) in diethyl ether (100 ml) and the mixture was stirred for 40 min at .T. The mixture was then concentrated in vacuo and the resulting solid was washed with diethyl ether to give the title salt (50 g, 119%) as a white solid which was used without further purification.

1H NMR: 2.66 (6H, s), 4.00-4.05 (2H, m), 4.24-4.28 (m, 1H), 4.34-4.38 (m, 2H).

Intermediate 27. tert-Butyl 3-dimethylaminoazetidine-1-carboxylate.

To a solution of Yudimethylazetidin-3-amine (Intermediate 28, 100 g, 1.0 mol) and triethylamine (487 ml, 3.5 mol) in CH ₂ Cl ₂ (500 ml) at 0° C. was added tert-butyl-( 2-methylpropan-2yl)oxycarbonyl carbonate (326 g, 1.5 mol). The mixture was then stirred at room temperature. for 5 hours. The mixture was then washed with water (4x500 ml) and the organic solution was dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by FCC gave the title compound (62 g, 31%).

Intermediate 28. Judimethylazetidine-3-amine.

1-Chloroethylcarbonochloridate (118 g, 0.83 mol) was added to a solution of 1-benzhydryl-K^dimethylazetidin-3-amine (Intermediate 29, 200 g, 0.75 mol) in dichloroethane (1 L) and the mixture was refluxed refrigerator at 100°C for 2 hours. The mixture was then concentrated in vacuo and the resulting residue was dissolved in CH ₃ OH (1 L) and the mixture was refluxed at 90°C for 2 hours. The mixture was then concentrated to obtain the above title of the compound, which was used in the next step without further purification.

Intermediate 29. 1-Benzhydryl-1-Udimethylazetidine-3-amine.

Aqueous dimethylamine (1 L, 33%) was added to a solution of (1-benzhydryl azetidin-3yl)methanesulfonate (Intermediate 30, 260 g, 0.82 mol) in CH ₃ CN (1 L) and the mixture was refluxed at 100° C during the night. The mixture was then cooled and the solvent was removed in vacuo. The mixture was partitioned between water (300 ml) and CH ₂ Cl ₂ (300 ml) and the layers were separated. The aqueous phase was extracted with CH ₂ Cl ₂ (3x500 ml). The combined organic solutions were dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by FCC gave the title compound (200 g, 92%) as a brown solid.

Intermediate 30: (1-Benzhydryl azetidin-3-yl)methanesulfonate.

A solution of methanesulfonyl chloride (115 g, 1.01 mol) in CH2Cl2 (500 ml) at 0°C was added dropwise to a solution of 1-benzhydryl azetidin-3-ol (Intermediate 31, 200 g, 0.84 mol) and triethylamine (119 g, 1.17 mmol) in CH2Cl2 (2 L) and the mixture was stirred at 0°C for 1 hour. The reaction was quenched until

- 47 046985 by adding aqueous NaHCO3. The phases were separated and the aqueous solution was extracted with CH2C12 (3x500 ml). The combined organic solutions were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound (260 g, 98%) as a white solid.

Intermediate 31: 1-Benzhydrylazetidin-3-ol.

DIPEA (129 g, 1 mol) was added at 0°C to a solution of 1-(benzhydrylamino)-3-chloropropan-2-ol (Intermediate 32, 276 g, 1 mol) in ethanol (2 L), then the mixture was boiled with reflux at 90°C overnight. The mixture was then concentrated in vacuo to give the title compound (179 g, 75%), which could be recrystallized from acetone and petroleum ether.

Intermediate 32: 1-(Benzhydrylamino)-3-chloropropan-2-ol.

2-(Chloromethyl)oxirane (92 g, 1 mol) was added dropwise at 0°C to a solution of diphenylmethanamine (183 g, 1 mol) in CH ₃ OH (1 L), then the mixture was stirred at room temperature. during the night. The mixture was then concentrated in vacuo to give the title compound (201 g, 73%), which was used in the next step without further purification.

Intermediate 33. N-(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-U-(2dimethylaminoethyl)-5-methoxy-N-methylbenzene-1,2, 4-triamine

A solution of NH ₄ Cl (45 mg, 0.85 mmol) in water (10 ml) was added in one portion to the stirred mixture of >(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl )-N-(2-dimethylaminoethyl)-2-methoxy-Nmethyl-5-nitrobenzene-1,4-diamine (Intermediate 34, 600 mg, 1.21 mmol) and iron (405 mg, 7.24 mmol) in ethanol (30 ml). The resulting mixture was stirred at 105°C for 3 hours. The mixture was then concentrated in vacuo and the resulting residue was mixed with DMF (10 ml) and purified by ion exchange chromatography using an SCX column. The title product was eluted from the column using 0.35 M methanolic ammonia in CH ₂ Cl ₂ and the pure fractions were concentrated in vacuo to give the title compound (530 mg, 94%) as a brown gum.

1H NMR: 2.16 (6H, d), 2.38 (2H, t), 2.66 (3H, d), 2.92 (2H, t), 3.66 (3H, s), 4.60 (2H, s), 6.78 (1H, s ), 6.92 (1H, s), 7.12 (1H, t), 7.27-7.4 (1H, m), 8.38 (1H, s), 8.43 (1H, d), 8.49 (1H, s), 8.83 (1H, d), 8.95 (1H, s); m/z: ES ⁺ MH ⁺ 467.

Intermediate 34. >(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-N-(2dimethylaminoethyl)-2-methoxy-N-methyl-5-nitrobenzene-1 ,4-diamine

NNN'-Trimethylethylenediamine (0.188 ml, 1.45 mmol) was added to the mixture of 5-chloro->(4-fluoro-2methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2 -amine (Intermediate 20, 500 mg, 1.21 mmol) and DIPEA (0.250 ml, 1.45 mmol) in DMA (5 ml) and the mixture was heated at 140 °C under microwave conditions for 0.5 h. The mixture was then diluted with CH ₃ OH and absorbed onto an SCX column. The column was washed with _CH3OH and eluted with a 1:1 mixture of methanolic ammonia in CH2C12. The appropriate fractions were concentrated in vacuo to give the title compound (624 mg, 104%) as an orange solid which was used without further purification.

1H NMR: 2.17 (6H, d), 2.89 (3H, d), 3.87-3.93 (3H, m), 6.84 (1H, s), 7.14 (1H, td), 7.31-7.38 (1H, m), 8.15 (1H, s), 8.39 (1H, d), 8.44 (1H, d), 8.69 (1H, s), 8.85 (1H, d), 8.95 (1H, s); m/z: ES ⁺ MH ⁺ 497.

Intermediate 35. 4-[(3aK,6aK.)-5-Methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,2c]pyrrol-1 -yl]-N-(5-chloro- 4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-6-methoxybenzene-1,3-diamine.

Mixture >[4-[(3aK,6aK.)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,2-c]pyrrol-1-yl]-2-methoxy-5nitrophenyl] -5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 36, 155 mg, 0.30 mmol), iron (100 mg, 1.79 mmol) and NH ₄ Cl (11.2 mg, 0.21 mmol) in ethanol (12 ml) and water (4 ml) was refluxed for 2 hours. The mixture was then cooled and filtered through decalite (a type of diatomaceous earth) and the filtrate was concentrated in vacuum to obtain a brown resin. As a result of purification by FCC eluting with 0-5% 7N. methanolic ammonia in CH2C12 gave the title compound (105 mg, 72%) as a gum.

1H NMR (CDCI3): 1.76-1.80 (1H, m), 2.03-2.20 (2H, m), 2.28 (3H, s), 2.48 (1H, dd), 2.59-2.63 (2H, m), 2.76-2.98 (2H, m), 3.46 (1H, dt), 3.78 (2H, s), 3.84 (3H, s), 4.07-4.10 (1H, m), 6.73 (1H, s), 6.94 (1H, td), 7.36 (1H, ddd), 7.51 (1H, s), 7.86 (1H, s), 8.35 (1H, s), 8.54 (1H, d), 8.65 (1H, d), 8.93 (1H, s); m/z: ES ⁺ MH ⁺ 491.29.

Intermediate 36 -5-nitrophenyl}-5-chloro-4-pyrazolo-[1,5-a]pyridin-3-yl-pyrimidin-2-amine.

(3aR,6aR)-5-Methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,2-c]pyrrole (Intermediate 37, 91 mg, 0.72 mmol) was added to mixtures of 5-chloro->(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5a]pyridin-3-ylpyrimidin-2-amine (Intermediate 20, 250 mg, 0.60 mmol) and DIPEA (0.334 ml, 1.93 mmol) in 2,2,2-trifluoroethanol (3 ml) and the mixture was heated at 140° C. under microwave conditions for 0.5 h. The mixture was then absorbed onto silica. As a result of purification by FCC eluting with 2% 7N. methanol ammonia in CH2Cl2 produced a material that was concentrated in vacuo and dissolved in CH3OH. The resulting solution was absorbed onto an SCX column and the column was washed with CH3OH, then eluted with 7N. methanol ammonia. The appropriate fractions were concentrated in vacuo to give the title compound (155 mg, 49%) as an orange/red tarry solid.

- 48 046985 ¹ H NMR (CDCI3): 1.89 (1H, dd), 2.04-2.19 (1H, m), 2.24 (3H, s), 2.30-2.39 (1H, m), 2.40-2.57 (2H, m) , 2.68 (1H, t), 2.98-3.11 (1H, m), 3.23 (1H, t), 3.51-3.63 (1H, m), 3.97 (3H, s), 4.36-4.48 (1H, m), 6.46 (1H, s), 6.90-7.02 (1H, m), 7.31-7.43 (2H, m), 8.38 (1H, s), 8.48 (1H, dd), 8.53-8.57 (1H, m), 8.82 (1H , s), 8.93 (1H, s); m/z: ES+MH+ 521.45.

Intermediate 37. (3aR,6aR)-5-Methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-b]pyrrole.

Palladium on carbon (10 g) under N2 was added to a solution of (3aR,6aR)-5-methyl-1-[(1R)-1-phenylethyl]2,3,3a,4,6,6a-hexahydropyrrolo[3,2 -c]pyrrole (Intermediate 38, 20 g, 0.087 mol) in ethanol (500 ml). The resulting mixture was hydrogenated at 70°C/45 psi. inch for 24 hours. The mixture was then filtered and the filtrate was concentrated in vacuo to give the title compound (10.9 g, 99%) as a solid.

1H NMR: 1.59-1.66 (1H, m), 1.86-1.95 (1H, m), 2.18 (s, 3H), 2.28-2.34 (2H, m), 2.46-2.47 (1H, m), 2.73 (2H, d), 3.00 (2H, m), 3.90 (2H, m).

Intermediate 38. (3aR,6aR)-5-Methyl-1-[(1R)-1-phenylethyl]-2,3,3a,4,6,6ahexahydropyrrolo[3,2-c]pyrrole.

37% aqueous formaldehyde (1.6 l) at room temperature. was added to a solution of (3aR,6aR)-1-[(1R)-1phenylethyl]-3,3a,4,5,6,6a-hexahydro-2H-pyrrolo[3,2-c]pyrrole (Intermediate 39, 108 g, 0.5 mol) in HCOOH (800 ml), then the mixture was stirred at 70-80°C for 2 hours. The mixture was then cooled to 0°C and basified with solid NaOH to a pH of approximately 13. This mixture was then extracted with CH ₂ Cl ₂ (2x2 l). The combined organic solutions were concentrated in vacuo. Purification by FCC eluting with a 2:1 to 1:10 hexanes/EtOAc gradient gave the title compound (80 g, 70%) as a red oil.

1H NMR (CDCl3): 1.36 (3H, d), 1.65 (1H, m), 1.85 (1H, m), 2.22 (3H, m), 2.32 (3H, s), 2.54 (1H, m), 2.68 ( 2H, m), 2.83 (1H, m), 3.10 (1H, m), 3.40 (1H, m), 7.21-7.33 (5H, m).

Intermediate 39. (3aR,6aR)-1-[(1R)-1-Phenylethyl]-3,3a,4,5,6,6a-hexahydro-2Hpyrrolo[3,2-c]pyrrole.

Solution of ethyl (3aR,6aR)-1-[(1R)-1-phenylethyl]-2,3,3a,4,6,6a-hexahydropyrrolo[3,2-c]pyrrole-5carboxylate (Intermediate 40, 300 g, 1.04 mol) in concentrated HCl (4 L, 37%) were refluxed overnight. The mixture was then cooled to 0°C and extracted with CH ₂ Cl ₂ (2x1 L). The aqueous solution was adjusted to a pH value of 12-13 using NaOH (solid). The combined organic solutions were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound (150 g, 67%) as a dark oil, which was used in the next step without further purification.

Intermediate 40. Ethyl (3aR,6aR)-1-[(1R)-1-phenylethyl]-2,3,3a,4,6,6a-hexahydropyrrolo[3,2-c]pyrrole-5-carboxylate.

A mixture of ethyl-H-(2-oxoethyl)-N-prop-2-enylcarbamate (Intermediate 41, 466 g, 2.7 mol) and 2-{[(A)-1-phenylethyl]amino}acetic acid (Intermediate compound 43A, 490 g, 2.7 mol) in toluene (4 L) was refluxed overnight. The resulting mixture was filtered and the filtrate was concentrated in vacuo. Purification by FCC eluting with 10:1 gasoline-EtOAc gave the title compound (300 g, 38%) as a red oil.

1H NMR (CDCl ₃ ): 1.10-1.40 (8H, m), 1.55 (1H, m), 1.90 (1H, m), 2.45 (1H, m), 2.77 (1H, m), 3.20-3.65 (5H, m), 4.10-4.20 (2H, m), 7.25-7.38 (5H, m).

Intermediate 41. Ethyl-N-(2-oxoethyl)-N-prop-2-enylcarbamate.

A solution of ethyl-H-(2,2-dimethoxyethyl)-H-prop-2-enylcarbamate (Intermediate 42, 1218 g, 2.79 mol) in HCOOH (4.2 L) was refluxed for 0.5 h. Then, in order to quench the reaction, crushed ice was added, the mixture was extracted with CH ₂ Cl ₂ (3x2 l). The combined organic solutions were washed with sat. NaHCO3 (3 L), dried (Na2SO4) and concentrated in vacuo to give the title compound (480 g, 50%) as a yellow oil.

1H NMR (CDCl3): 1.15-1.32 (3H, m), 3.89-4.00 (4H, m), 4.07-4.16 (2H, m), 5.10 (2H, m), 5.73 (1H, m), 9.53 (1H , s).

Intermediate 42. Ethyl H-(2,2-dimethoxyethyl)-N-prop-2-enylcarbamate.

Ground KOH (1417 g, 25.3 mol) was added in portions to a solution of ethyl N-(2,2dimethoxyethyl)carbamate (Intermediate 43, 1123 g, 6.3 mol) in toluene (5 L). Then at room temperature benzyltriethyl ammonium chloride (14.0 g, 0.06 mol) and allyl bromide (532 g, 4.4 mol) were added. The mixture was then stirred at room temperature. during the night. The mixture was then filtered and the reaction mixture was washed with brine (2 L), dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound (1218 g, 89%) as a yellow oil.

1H NMR (CDCl3): 1.23 (3H, s), 3.28 (2H, s), 3.36 (6H, s), 3.92 (2H, d), 4.12 (2H, s), 4.47 (1H, d), 5.08 ( 2H, d), 5.73 (1H, s).

Intermediate 43. Ethyl N-(2,2-dimethoxyethyl)carbamate.

- 49 046985

A solution of NaOH (578.4 g, 14.46 mol) in H2O (2 L) was added to a solution of 2,2-dimethoxyethanamine (800 g, 7.6 mol) in toluene (2 L) and the resulting mixture was cooled to 0°C using an ice bath. Ethyl chloroformate (825 g, 7.6 mol) was added dropwise while maintaining the temperature at approximately 10°C. The mixture was then stirred at room temperature. during the night. The phases were then separated and the aqueous solution was saturated with solid NaCl. This solution was then extracted with toluene (3 x 1.25 L). The combined organic solutions were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound (1.123 kg, 83%) as a colorless oil.

1H NMR (CDCl ₃ ): 1.17 (3H, t), 3.14 (2H, s), 3.32 (6H, s), 4.02-4.07 (2H, m), 4.30 (1H, t).

Intermediate connection 43A. 2-{[(III)-1-Phenylethyl]amino}acetic acid.

Methyl 2-{[(III)-1-phenylethyl]amino}acetate (Intermediate 44, 587.0 g, 3.0 mol) was refluxed in aqueous KOH (3.36 g, 0.06 mol dissolved in 2.5 liters of water) overnight. The phases were then separated and the aqueous solution was washed with EtOAc (3x1 L). The combined organic solutions were concentrated in vacuo to give the title compound (490 g, 90%) as a white solid.

1H NMR: 1.48 (3H, d), 2.89 (1H, d), 3.00 (1H, d), 4.20 (1H, m), 7.37-7.43 (5H, m).

Intermediate 44. Methyl 2-{[(III)-1-phenylethyl]amino}acetate.

Methyl 2-bromoacetate (621 g, 4.1 mol) at r.t. was added dropwise to a mixture of (1C)-1-phenylethanamine (410 g, 3.4 mol) and triethylamine (377 g, 3.7 mol) in EtOAc (4.5 L). The mixture was then stirred at 50-60°C overnight, then cooled to room temperature. The mixture was then washed with water (800 ml) and brine (100 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound (587 g, 90%) as a yellow oil.

1H NMR (CDCl ₃ ): 1.29 (3H, d), 3.13-3.24 (2H, m), 3.60 (3H, s), 3.68-3.71 (1H, m), 7.13-7.26 (5H, m).

Intermediate 45. N-(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4methoxy-6-(5-methyl-2,5-diazaspiro[3.4]octane -2-yl)benzene-1,3-diamine.

Mixture of 5-chloro-H-[2-methoxy-4-(5-methyl-2,5-diazaspiro[3.4]octan-2-yl)-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridine -3-ylpyrimidin-2-amine (Intermediate 46.95 mg, 0.18 mmol), iron (61 mg, 1.09 mmol) and NH4Cl (7.32 mg, 0.14 mmol) were refluxed at ethanol (10.5 ml) and water (3.5 ml) for 2 hours. The mixture was cooled and filtered through diatomaceous earth (Celite™). The filtrate was concentrated in vacuo and the residue was dissolved in CH ₂ Cl ₂ . This solution was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. As a result of purification by FCC eluting with 2-6% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (30 mg, 34%) as a brown gum; m/z: ES ⁺ MH ⁺ 491.5.

Intermediate 46. 5-Chloro-H-[2-methoxy-4-(5-methyl-2,5-diazaspiro[3.4]octan-2-yl)-5nitrophenyl]-4-pyrazolo[^^pyridin-3 - ilpyrimidin-2-amine.

A mixture of 5-methyl-2,5-diazaspiro[3.4]octane dihydrochloride salt (Intermediate 47, 400 mg) in CH ₃ OH/water was absorbed onto an SCX column. The column was washed with CH3OH and eluted with methanolic ammonia. Fractions containing the product were combined and concentrated (note: product is volatile). 5-Chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5a]pyridin-3-ylpyrimidin-2-amine mixture (Intermediate 20, 250 mg, 0.60 mmol ), 5-methyl-2,5diazaspiro[3.4]octane (91 mg, 0.72 mmol) and DIPEA (0.365 ml, 2.11 mmol) in DMA (3 ml) were heated under microwave conditions at 140°C for 0.5 h. The mixture was then diluted with CH3OH and absorbed onto an SCX column. The column was washed with CH ₃ OH and eluted with a 1:1 mixture of methanolic ammonia and CH ₂ Cl ₂ . Fractions containing product were combined and concentrated to give a solid. This solid was suspended in CH ₃ OH, filtered, washed with diethyl ether and dried to give the title compound (267 mg, 85%) as a red solid.

¹ H NMR: 1.63-1.78 (2H, m), 2-2.12 (2H, m), 2.41 (3H, s), 2.69 (2H, t), 3.77 (2H, d), 3.90 (3H, s), 4.13 (2H, d), 6.30 (1H, s), 7.14 (1H, td), 7.34 (1H, t), 8.12 (1H, s), 8.41-8.46 (2H, m), 8.74 (1H, s) , 8.86 (1H, d), 8.96 (1H, s); m/z: ES ⁺ MH ⁺ 521.46.

Intermediate 47. 5-Methyl-2,5-diazaspiro[3.4]octane dihydrochloride salt.

M solution of HCl in EtOAc (120 ml) was prepared by adding acetyl chloride (34 ml) to a solution of ethanol (28 ml) and EtOAc (58 ml). This solution was then added to a mixture of 2-benzyl-5-methyl-2,5diazaspiro[3.4]octane (Intermediate 48, 48 g, 221.89 mmol) and Pd(OH) ₂ (34 g, 20% on carbon) in 1.5 l CH ₃ OH. The mixture was then stirred at 30° C. under 55 psi H ₂ pressure. inch for 24 hours. The mixture was then filtered and the filtrate was concentrated in vacuo to give the title salt (42.7 g, 96%) as a yellow oil.

^1H NMR ^-methanol: 1.98-2.11 (2H, m), 2.53 (2H, t), 3.02 (3H, s), 3.38 (2H, t), 4.17 (2H, d), 4.68 (2H, d ).

Intermediate 48. 2-Benzyl-5-methyl-2,5-diazaspiro[3.4]octane.

Paraformaldehyde (70.91 g, 787 mmol) and triethylamine (119.5 g, 1.18 mol) were added to a mixture of 2-benzyl-2,5-diazaspiro[3.4]octane dihydrochloride (Intermediate 49, 65 g, 236, 2 mmol) in

- 50 046985

1,2-dichloroethane (700 ml) and the mixture was stirred for 1 hour at 10°C. Sodium triacetoxyborohydride (110.8 g, 1.18 mol) was then added and the mixture was stirred for 12 hours at 15°C. The mixture was then filtered and the filter cake washed with CH ₂ Cl ₂ (3x500 ml). The combined organic solutions were washed with brine (500 mL), dried (MgSO ₄ ) and concentrated in vacuo to give the title compound (51.1 g, 94%) as a yellow oil.

^1H NMR (300 MHz, CDCl ₃ ): 1.75 (2H, m), 2.16 (2H, m), 2.49 (3H, s), 2.64 (2H, d), 3.10 (2H, d), 3.28 (2H, d), 3.66 (2H, s), 7.22-7.62 (5H, m).

Intermediate 49. 2-Benzyl-2,5-diazaspiro[3.4]octane dihydrochloride.

M solution of HCl in EtOAc (2 L) was added to a solution of tert-butyl-2-benzyl-2,5-diazaspiro[3.4]octane5-carboxylate (Intermediate 50, 195 g, 644.8 mmol) in EtOAc (0.5 l) and the mixture was stirred for 12 hours. The resulting solid was collected by filtration and washed with t-butyl methyl ether (2 L) to obtain the title salt (170 g, 96%) as a white solid.

1H NMR ^-methanol): 2.04-2.11 (2H, m), 2.41 (2H, t), 3.39 (2H, t), 4.33 (2H, s), 4.81-4.88 (2H, m), 7.497.58 ( 5H, m).

Intermediate 50. tert-Butyl-2-benzyl-2,5-diazaspiro[3.4]octane-5-carboxylate.

A solution of CBr ₄ (369.5 g, 1.115 mol) in 1 L of CH ₂ Cl ₂ at 0°C was added dropwise to a solution of tert-butyl2-[(benzylamino)methyl]-2-(hydroxymethyl)pyrrolidine-1-carboxylate ( Intermediate 51, 178.5 g, 555 mmol) and triphenylphosphine (292 g, 1.115 mol) in CH ₂ Cl ₂ (1.8 L). The resulting mixture was stirred at room temperature. for 2 hours, then concentrated in vacuo. The residue was suspended in a mixture of CH3CN (2 L) and triethylamine (563.5 g, 5.57 mol) and refluxed at 80°C for 24 hours. The mixture was then concentrated in vacuo. Purification by FCC eluting with 1:1 gasoline-EtOAc gave the title compound (97.5 g, 58%) as a yellow oil.

1H NMR (300 MHz, CDCl ₃ ): 1.47-1.72 (11H, m), 2.30 (2H, m), 3.19 (2H, d), 3.31-3.47 (2H, m), 3.82-4.12 (4H, m) , 7.22-7.28 (5H, m).

Intermediate 51: 2-[(Benzylamino)methyl]-2-(hydroxymethyl)pyrrolidine-1-carboxylate.

Borane dimethyl sulfide (170 ml, 1.7 mol) was added to a solution of tert-butyl-2-benzyl-3-oxo-2,5diazaspiro[3.4]octane-5-carboxylate (Intermediate 52, 179 g, 567 mmol) in 1.8 L of THF and the mixture was refluxed at 80°C for 12 hours. The reaction was then quenched by adding CH3OH (1 L) and water (1.5 L). The phases were then separated and the aqueous solution extracted with EtOAc (3 x 1 L), then the combined organic solutions were washed with brine (3 x 1 L), dried (MgSO ₄ ) and concentrated in vacuo to give the title compound (119 g, 66%) as a yellow oil .

1H NMR (CDCl ₃ ): 1.47 (10H, m), 1.55-1.78 (3H, m), 2.06 (1H, m), 2.57 (2H, d), 3.17 (1H, m), 3.35 (2H, m) , 3.37 (1H, m), 3.75-3.87 (3H, m), 7.23-7.40 (5H, m).

Intermediate 52. tert-Butyl-2-benzyl-3-oxo-2,5-diazaspiro[3.4]octane-5carboxylate.

n-Butyllithium (268.7 ml, 0.672 mmol, 2.5 M in hexane) was added at -70°C under N2 to a solution of diisopropylamine (70 g, 691.7 mmol) in dry THF (1.5 L), then the mixture was stirred for 1 hour at -70°C. A solution of 1-tert-butyl-2-methyl-pyrrolidine-1,2dicarboxylate (Intermediate 53, 140 g, 610 mmol) in anhydrous THF (360 ml) was then added dropwise at -70°C. After stirring at -70°C for 1 hour, a solution of 2-(benzylamino)acetonitrile (Intermediate 54, 45.9 g, 305.7 mmol) in anhydrous THF (360 ml) was added dropwise at -70°C over time period of 1 hour. Then the resulting mixture was heated to room temperature, then stirred for 12 hours. Then saturated. NH ₄ Cl (1.5 L) and the resulting phases were separated. The aqueous solution was extracted with EtOAc (3x1 L). The combined organic solutions were washed with brine (3x1 L), dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC, eluting with 2:1 petroleum ether/EtOAc, gave the title compound (75.5 g, 76%) as a yellow oil.

1H NMR (CDCl ₃ ): 1.44 (9H, m), 1.77 (1H, m), 1.93 (1H, m), 2.04 (1H, m), 2.37 (1H, m), 3.00 (1H, m), 3.40 -3.67 (3H, m), 3.95 (1H, m), 4.25-4.89 (1H, m), 7.21-7.36 (5H, m).

Intermediate 53: 1-tert-Butyl-2-methyl-pyrrolidine-1,2-dicarboxylate.

K ₂ CO ₃ (1.1 kg, 8.0 mol) and CH ₃ I (659 g, 4.65 mol) at RT. was added to a solution of 1-[(2-methylpropan2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid (500 g, 2.32 mol) in DMF (2.5 L) and the mixture was stirred for 12 hours, then filtered. The filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (2 L) and washed with water (2x1 L), brine (1 L), dried (MgSO ₄ ) and concentrated in vacuo to give the title compound (417.8 g, 96%) as a yellow oil .

1H NMR (CDCl ₃ ): 1.37 (9H, m), 1.72-1.84 (3H, m), 2.15 (1H, m), 3.26-3.51 (2H, m), 3.65 (3H, s), 4.17 (1H, m).

Intermediate 54: 2-(Benzylamino)acetonitrile.

A solution of ClCH ₂ CN (316 g, 4.19 mol) in EtOAc (200 ml) was added dropwise to benzylamine (900 g,

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8.40 mol) with vigorous stirring of the mixture. The mixture was carefully heated to 45°C for 0.5 h and the white precipitate was removed by filtration. The filtrate was concentrated in vacuo to give the title compound (606 g, 99%) as a yellow oil.

1H NMR (CDCl ₃ ): 3.56 (2H, s), 3.94 (2H, s), 7.28-7.40 (5H, m).

Intermediate 55. N-(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4methoxy-6-(1-methyl-3,6-dihydro-2H-pyridine -4-yl)benzene-1,3-diamine.

Mixture of 5-chloro-N-[2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridine -3-ylpyrimidin-2-amine (Intermediate 56, 470 mg, 0.96 mmol), iron (320 mg, 5.73 mmol) and NH4Cl (35.8 mg, 0.67 mmol) in ethanol (19 ml ) and water (6.33 ml) were refluxed for 4 hours. The mixture was then cooled and concentrated in vacuo to obtain a thick suspension, which was triturated with 10% CH ₃ OH in CH ₂ Cl ₂ (50 ml) for 15 min. The mixture was then filtered and a small amount of sat. was added to the filtrate. _NaHCO3 . The resulting phases were separated and the aqueous solution was extracted with 10% CH3OH in CH ₂ Cl ₂ (50 ml). The combined organic solutions were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 2.5% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (387 mg, 88%) as a yellow foam.

1H NMR: 2.31 (3H, s), 2.38-2.44 (2H, m), 2.61 (2H, t), 3.02 (2H, dd), 3.68 (3H, s), 4.33 (2H, d), 5.72-5.76 (1H, m), 6.66 (1H, s), 7.08 (1H, s), 7.14 (1H, td), 7.35-7.43 (1H, m), 8.41 (1H, s), 8.44 (1H, s), 8.49 (1H, d), 8.84 (1H, d), 8.96 (1H, s); m/z: ES+MH+ 462.5.

Intermediate 56. 5-Chloro-N-[2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5nitrophenyl]-4-pyrazolo[1,5-a] pyridin-3-ylpyrimidin-2-amine.

A mixture of 3-(2,5-dichloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine (Intermediate 21, 575 mg, 1.86 mmol) and 2-methoxy-4-(1-methyl-3, 6-Dihydro-2H-pyridin-4-yl)-5-nitroaniline (Intermediate 3, 490 mg, 1.86 mmol) was stirred in THF (30 ml) and cooled in an ice/water bath. Lithium bis(trimethylsilyl)amide (4.10 mL, 4.10 mmol, 1 M in THF) was then added dropwise and the mixture was stirred for 1 hour. CH3OH was added and the mixture was concentrated in vacuo. The crude material was suspended in CH ₃ OH and the mixture was filtered. The collected solid was washed with CH ₃ OH and diethyl ether and filter dried to obtain the title compound (660 mg, 72%) as a yellow powder.

1H NMR: 2.29 (3H, s), 2.30-2.38 (2H, m), 2.58 (2H, t), 2.97 (2H, dd), 3.96 (3H, s), 5.60-5.68 (1H, m), 7.00 (1H, s), 7.16 (1H, td), 7.36-7.45 (1H, m), 8.49-8.56 (3H, m), 8.87 (1H, d), 8.90 (1H, s), 8.97 (1H, s ); m/z: ES ⁺ MH ⁺ 492.4.

Intermediate 57. 2-(4-{2-Amino-4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3ylpyrimidin-2-yl)amino]-5-methoxyphenyl}piperazine-1 -yl)->>dimethylacetamide.

Mixture of 2-(4-{4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-5-methoxy-2nitrophenyl}piperazin-1-yl) ->>dimethylacetamide (Intermediate 58, 0.234 g, 0.41 mmol), iron (0.139 g, 2.48 mmol) and NH ₄ Cl (0.015 g, 0.29 mmol) in ethanol (10 ml) and water ( 3.33 ml) was refluxed for 4 hours. The mixture was then allowed to cool to room temperature, filtered and the filtrate concentrated in vacuo. Purification by ion exchange chromatography using an SCX column and eluting with 1 M methanol ammonia gave a brown gum after concentrating the appropriate fractions. Further purification by FCC eluting with 0-5% CH ₃ OH in CH ₂ Cl ₂ gave the title compound (0.19 g, 86%) as a yellow foam.

1H NMR (CDCl3): 2.72 (4H, s), 2.93-3.01 (7H, m), 3.13 (3H, s), 3.27 (2H, s), 3.65-3.83 (2H, m), 3.84 (3H, s ), 6.71 (1H, s), 6.96 (1H, td), 7.38 (1H, ddd), 7.55 (1H, s), 7.92 (1H, s), 8.36 (1H, s), 8.57 (1H, dt) , 8.61-8.68 (1H, m), 8.94 (1H, s); m/z: ES'MH' 536.53.

Intermediate 58. 2-(4-{4-[(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2yl)amino]-5-methoxy-2-nitrophenyl}piperazine-1 -yl)->>dimethylacetamide.

DIPEA (0.105 ml, 0.60 mmol) was added to a mixture of 5-chloro->(4-fluoro-2-methoxy-5-nitrophenyl)-4pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine ( Intermediate 20, 207 mg, 0.5 mmol) and >>dimethyl-2-piperazin-1-ylacetamide (86 mg, 0.50 mmol) in 2,2,2-trifluoroethanol (2.5 ml). The mixture was heated under microwave conditions at 140°C for 1 hour, then cooled to room temperature. The mixture was purified directly by ion exchange chromatography using an SCX column and eluting with 7 M methanol ammonia to provide the corresponding crude product fractions after concentration. Purification by FCC eluting with 0-5% CH3OH in CH2Cl2 then gave the title compound (234 mg, 83%) as an orange foam.

1H NMR (CDCl3): 2.71-2.78 (4H, m), 2.97 (3H, s), 3.09 (3H, s), 3.11-3.18 (4H, m), 3.26 (2H, s), 3.99 (3H, s ), 6.66 (1H, s), 6.97 (1H, td), 7.35-7.42 (1H, m), 7.52 (1H, s), 8.41 (1H, s), 8.49 (1H, d), 8.56 (1H, d), 8.92 (1H, s), 9.02 (1H, s); m/z: ES ⁺ MH ⁺ 566.52.

Intermediate 59. ^)-tert-Butyl->[1-(4-{2-amino-4-[(5-chloro-4-pyrazolo[1,5a]pyridin-3-ylpyrimidin-2-yl)amino ]-5-methoxyphenyl}piperazin-1-yl)-1-oxopropan-2-yl]carbamate.

Mixture of ^)-tert-butyl->[1-(4-{4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-5

- 52 046985 methoxy-2-nitrophenyl}piperazin-1-yl)-1-oxopropan-2-yl]carbamate (Intermediate 60, 100 mg, 0.15 mmol), iron (51.4 mg, 0.92 mmol ) and NH ₄ Cl (5.74 mg, 0.11 mmol) were refluxed in ethanol (3 ml) and water (1 ml) for 1 hour. Purification by ion exchange chromatography using an SCX column and eluting 7M methanolic ammonia provided material which was further purified by FCC eluting with 0-5% CH ₃ OH in CH ₂ Cl ₂ to give the title compound (65 mg, 68%) as a yellow solid; m/z: ES ⁺ MH ⁺ 622.58.

Intermediate 60. ^)-tert-Butyl-N[1-(4-{4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3ylyl-pyrimidin-2-yl)amino]- 5-methoxy-2-nitrophenyl}piperazin-1-yl)-1-oxopropan-2-yl]-carbamate.

DIPEA (0.105 ml, 0.60 mmol) was added to a mixture of 5-chloro-M-(4-fluoro-2-methoxy-5-nitrophenyl)-4pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 20, 207 mg, 0.5 mmol) and (R)-tert-butyl 1-oxo-1-(piperazin-1-yl)propan-2-ylcarbamate (129 mg, 0.50 mmol) in 2 ,2,2-trifluoroethanol (2.5 ml). The mixture was heated under microwave conditions at 140°C for 1 hour, then cooled to room temperature. The mixture was purified directly by ion exchange chromatography using an SCX column and eluting with 7 M methanol ammonia to obtain the crude material. Purification by FCC eluting with 0-5% CH3OH in CH ₂ Cl ₂ then gave the title compound (110 mg, 34%) as a solid/resin; m/z: ES ⁺ MH ⁺ 552.59.

Intermediate 61. K-(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-illirimidin-2-yl)-4-[(38)3-dimethylaminopyrrolidin-1-yl]-6-methoxybenzene - 1,3-diamine

A mixture of 5-chloro-N-[4-[(3 S)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin- 2-amine (Intermediate 62, 295 mg, 0.58 mmol), iron (194 mg, 3.48 mmol) and NH ₄ Cl (23 mg, 0.43 mmol) were refluxed in ethanol (12 ml) and water (4 ml) for 1.5 hours. The mixture was then cooled and concentrated in vacuo. The residue was triturated with 10% CH3OH in CH2Cl2 (25 ml) for 15 min and then filtered. The residue was triturated again with 10% CH3OH in CH ₂ Cl ₂ (25 ml) and filtered. The combined filtrates were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. As a result of purification by FCC eluting with 2% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (260 mg, 94%) as a yellow gum.

^1H NMR: 1.73-1.86 (1H, m), 2.01-2.12 (1H, m), 2.20 (6H, s), 2.81-2.91 (1H, m), 2.92-3.05 (2H, m), 3.16 (1H , dd), 3.2-3.27 (1H, m), 3.67 (3H, s), 4.25 (2H, d), 6.71 (1H, s), 6.93 (1H, s), 7.12 (1H, td), 7.3- 7.37 (1H, m), 8.36 (1H, s), 8.38-8.46 (2H, m), 8.82 (1H, dt), 8.94 (1H, s); m/z: ES ⁺ MH ⁺ 479.5.

Intermediate 62. 5-Chloro-N-{4-[(3S)-3-dimethylαminopyrrolidin-1-yl]-2-methoxy-5nitrophenyl}-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin- 2-am.

3S-N,N-Dimethylpyrrolidin-3-amine (0.092 ml, 0.72 mmol) was added to the suspension of 5-χλορ-Ν-(4fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a ]pyridin-3-ylpyrimidin-2-amine (Intermediate 20, 250 mg, 0.60 mmol) and DIPEA (0.125 ml, 0.72 mmol) in DMA (3 ml) and the mixture was heated at 140°C under microwave conditions radiation for 0.5 h. The mixture was then diluted with CH3OH and absorbed on an SCX column. The column was washed with CH3OH and then eluted with a 1:1 mixture of 7 M methanol ammonia and CH ₂ Cl ₂ . The corresponding fractions were concentrated and further purified by FCC, eluting with 2% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (300 mg, 98%) as an orange foam.

1H NMR: 1.75-1.95 (1H, m), 2.09-2.30 (7H, m), 2.72-2.87 (1H, m), 3.11-3.27 (3H, m), 3.42-3.56 (1H, m), 3.90 ( 3H, s), 6.57 (1H, s), 7.13 (1H, t), 7.26-7.41 (1H, m), 8.09 (1H, s), 8.28-8.50 (2H, m), 8.67 (1H, s) , 8.84 (1H, d), 8.95 (1H, s); m/z: ES ⁺ MH ⁺ 509.5.

Intermediate 63. N-(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3 -diamine

A mixture of 5-chloro-N[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3ylpyrimidin-2-amine (Intermediate 64, 775 mg, 1.57 mmol), iron (525 mg, 9.40 mmol) and NH ₄ Cl (62.8 mg, 1.17 mmol) were refluxed in ethanol (21 ml) and water (7 ml) for 2 hours. The mixture was then cooled and filtered through diatomaceous earth (Celite™). The filtrate was concentrated in vacuo and then dissolved in CH ₂ Cl ₂ . This solution was washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. As a result of purification by FCC eluting with 2-6% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (480 mg, 66%) as a brown gum.

1H NMR: 2.26 (3H, s), 2.52 (4H+DMSO, m), 2.89 (4H, t), 3.68 (3H, s), 4.35 (2H, d), 6.73 (1H, s), 6.99 (1H , d), 7.13 (1H, td), 7.28-7.39 (1H, m), 8.38 (1H, d), 8.39-8.46 (2H, m), 8.82 (1H, d), 8.95 (1H, s); m/z: ES ⁺ MH ⁺ 465.5.

Intermediate 64. 5-Chloro-N[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-4pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine.

1-Methylpiperazine (0.267 ml, 2.41 mmol) was added to the suspension of 5-chloro-N(4-fluoro-2-methoxy-5nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2- amine (Intermediate 20, 500 mg, 1.21 mmol) in 2,2,2-trifluoroethanol (6 ml). The mixture was heated under microwave conditions at

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140°C for 1 hour. The mixture was then loaded onto an SCX column and the column was washed with CH3OH. The column was then eluted with 2 M methanolic ammonia and the appropriate fractions were combined and concentrated in vacuo. Further purification by FCC eluting with 0-10% CH3OH in CH ₂ Cl ₂ gave the title compound (596 mg, 100%) as an orange foam.

^1H NMR ( _CDCl3 ): 2.37 (3H, s), 2.57-2.68 (4H, m), 3.08-3.14 (4H, m), 4.00 (3H, s), 6.64 (1H, s), 6.98 (1H , t), 7.34-7.43 (1H, m), 7.53 (1H, s), 8.41 (1H, s), 8.49 (1H, d), 8.53-8.6 (1H, m), 8.93 (1H, s), 9.04 (1H, s); m/z: ES+ MH+ 495.

Intermediate 65. 2-{[5-Amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4pyrazolo[1,5-a]pyridin-3-ylpyrimidin-5-carbonitrile.

Mixture of X'-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-methoxy-6-(4-methylpiperazin1-yl)benzene-1,3-diamine (Intermediate 63, 157 mg, 0.34 mmol), zinc (2.209 mg, 0.03 mmol), tris-(dibenzylideneacetone) dipalladium(0) (30.9 mg, 0.03 mmol), dicyclohexyl(2',4',6'triisopropylbiphenyl-2-yl)phosphine (XPhos, 32.2 mg, 0.07 mmol) and dicyanozinc (23.8 mg, 0.20 mmol) were placed in a reaction tube under N ₂ and then degassed DMA (0.9 ml). The resulting suspension was stirred to 95°C for 1.5 hours. The mixture was then diluted with EtOAc and washed five times with water, then with brine. The solution was then dried (MgSO ₄ ) and concentrated in vacuo. The residue was triturated with diethyl ether and the resulting solid was collected by filtration and washed with diethyl ether. The solid was then dissolved in a mixture of CH ₂ Cl ₂ and CH ₃ OH and the solution was allowed to flow through a SPEPL-Thiol MP SPE stratospheres cartridge (available from Polymer Laboratories) by gravity. The resulting solution was concentrated in vacuo to give the title compound (87 mg, 57%) as a yellow solid.

1H NMR (100°C): 2.28 (3H, s), 2.49-2.58 (4H, m), 2.90-2.98 (4H, m), 3.70 (3H, s), 4.28 (2H, br s), 6.77 ( 1H, s), 6.99 (1H, s), 7.14 (1H, t), 7.37 (1H, t), 8.37 (1H, d), 8.55 (1H, s), 8.78 (1H, d), 8.85 (1H , s), 8.92 (1H, s); m/z: ES+ MH+ 456.4.

Intermediate 66. N-[4-(III-Indol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(4methylpiperazin-1-yl)benzene-1,3-diamine.

A solution of NH ₄ Cl (0.021 g, 0.38 mmol) in water (3 ml) was added in one portion to the stirred suspension of 4-(III-indol-3-yl)-N-[2-methoxy-4-(4-methylpiperazine -1-yl)-5-nitrophenyl]pyrimidin-2-amine (Intermediate 67, 0.235 g, 0.51 mmol) and iron (0.171 g, 3.07 mmol) in ethanol (9 ml) and the mixture was stirred at 105 °C for 18 hours. The mixture was then concentrated in vacuo and the resulting residue was dissolved in DMF (20 ml). Purification by ion exchange chromatography using an SCX column eluting with 0.35 M methanol ammonia in CH ₂ Cl ₂ and concentrating the appropriate fractions gave the title compound (0.206 g, 94%) as a yellow solid; m/z: ES ⁺ MH+ 430.51.

Intermediate 67. 4-(III-Indol-3-yl)-N-[2-methoxy-4-(4-methylpiperazin-1-yl)-5nitrophenyl]pyrimidin-2-amine.

Mixture of 1-methylpiperazine (148 mg, 1.48 mmol), N(4-fluoro-2-methoxy-5-nitrophenyl)-4-(III-indol-3yl)pyrimidin-2-amine (Intermediate 68, 224 mg , 0.59 mmol) and trifluoroethanol (5 ml) were sealed in a microwave tube and heated under microwave conditions to 120°C for 1 hour and then cooled to room temperature. The mixture was then concentrated in vacuo. Trituration of the resulting brown gum with ethanol and then diethyl ether gave a solid, which was collected by filtration and dried under vacuum to give the title compound (89 mg, 33%) as a pale brown solid.

^1H NMR: 3.02-3.13 (4H, m), 4.00 (3H, s), 6.86 (1H, s), 7.08 (1H, t), 7.18 (1H, t), 7.31 (1H, d), 7.45 ( 1H, d), 8.08 (1H, s), 8.33 (2H, dd), 8.82 (1H, d), 11.81 (1H, s); m/z: ES ⁺ MH ⁺ 460.5.

Intermediate 68. No. (4-Fluoro-2-methoxy-5-nitrophenyl)-4-(III-indol-3-yl)pyrimidin2-amine

p-Toluenesulfonic acid hydrate (225 mg, 1.18 mmol) was added in one portion to a mixture of 4-fluoro-2-methoxy-5-nitroaniline (Intermediate 23, 200 mg, 1.07 mmol) and 3-(2-chloropyrimidine -4-yl)-III-indole (247 mg, 1.07 mmol) in 2-pentanol (10 ml). The resulting mixture was then stirred at 120°C for 18 hours. The resulting precipitate was collected by filtration, washed with 2-pentanol (5 ml) and dried in vacuum to obtain a yellow solid. The solid was triturated with CH3CN to give a solid, which was collected by filtration and dried in vacuo to give the title compound (224 mg, 55%) as a yellow solid;

- 54 046985 m/z: ES ⁺ MH ⁺ 380.21.

Intermediate 69: 4-Methoxy-6-(4-methylpiperazin-1-yl)-I-(4-pyrazolo[1,5a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine.

[(Z)-3-(dimethylamino)-3-pyrazolo[1,5-a]pyridin-3-yl-prop-2enylidene]-dimethylammonium hexafluorophosphate solution (Intermediate 70, 116 mg, 0.3 mmol) in 2-methoxyethanol (2 ml) at room temperature. under N ₂ was added dropwise to a stirred solution of 1-(5-amino-2-methoxy-4-(4methylpiperazin-1-yl)phenyl)guanidine (Intermediate 72, 84 mg, 0.30 mmol) and 1,1, 3,3-Tetramethylguanidine (0.056 ml, 0.45 mmol) in 2-methoxyethanol (2 ml). The resulting solution was sealed in a microwaving tube and heated to 120°C for 0.25 h, then cooled to room temperature. Additional 1,1,3,3-tetramethylguanidine (0.056 mL, 0.45 mmol) was then added and the mixture was stirred at 120°C for 0.25 h, then at 140°C for 0.25 h. The mixture was cooled , diluted with EtOAc (10 ml) and washed with water (2x5 ml). The aqueous solution was extracted with EtOAc (5 ml) and the organic solution was washed with water (2x3 ml). The combined organic solutions were dried (MgSO ₄ ) and concentrated in vacuo. As a result of purification by FCC eluting with 1.5-5% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (69 mg, 53%) as a yellow foam.

^1H NMR: 2.25 (3H, d), 2.51 (4H, m), 2.87 (4H, t), 3.73 (3H, s), 4.37 (2H, s), 6.72 (1H, s), 7.07 (1H, m), 7.22 (1H, d), 7.33 (1H, s), 7.40 (1H, m), 7.98 (1H, s), 8.31 (1H, d), 8.52 (1H, d), 8.76 (1H, s ), 8.79 (1H, d); m/z: ES+MH+431.

Intermediate 70. [(2)-3-(dimethylamino)-3-pyrazolo[1,5a]pyridin-3-yl-prop-2-enylidene]dimethylammonium hexafluorophosphate.

Dimethylamine (24.0 ml, 48.0 mmol, 2 M in THF) at r.t. under N2 was added in one portion to a suspension of (Z)-N-(3-chloro-3-(pyrazolo[1,5-a]pyridin-3-yl)allylidene)-N-methylmethanaminium hexafluorophosphate (Intermediate 71, 6.07 g, 16 mmol) in CH ₃ OH (40 ml). The resulting solution was stirred at room temperature. for 0.25 h, then stored in the refrigerator overnight. Crystals were obtained and collected, washed with CH3OH at -50°C and THF, then dried by aspiration under N2. Two batches of crystals were collected to provide the title compound (5.29 g, 85%) as a beige crystalline solid; m/z: ES ⁺ M ⁺ 244.

Intermediate 71. Hexafluorophosphate N)-N-(3-chloro-3-(pyrazolo[1,5-a]pyridin-3yl)allylidene)-N-methylmethanaminium.

POCl ₃ (0.951 ml, 10.20 mmol) at 20°C under N2 was added to a solution of (E)-3-(dimethylamino)-1(pyrazolo[1,5-a]pyridin-3-yl)prop-2- en-1-one (2.153 g, 10 mmol) in CH ₂ Cl ₂ (15 ml) (using ice/water cooling) for a period of 3 minutes. The resulting solution was stirred at room temperature. for 0.5 h and then concentrated in vacuo. The residue was dissolved in a minimal amount of CH ₃ OH (100 ml). This solution was added over a period of 2 minutes to a solution of sodium hexafluorophosphate (3.36 g, 20.00 mmol) in CH3OH (40 ml). After 5 min, the precipitate was collected by filtration, washed well with CH3OH cooled to -50°C and dried by aspiration under N2 to obtain the title compound (3.40 g, 90%) as a yellow powder, which was used in the next step without additional cleaning.

^1H NMR: 3.63 (6H, d), 7.36 (2H, m), 7.71-7.90 (1H, m), 8.45 (1H, d), 8.81 (1H, d), 9.05 (2H, d); m/z: ES ⁺ M+ 234.

Intermediate 72: 1-[5-Amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]guanidine.

A mixture of 1-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]guanidine (Intermediate 73, 1.47 g, 4.58 mmol) and 10% Pd on carbon (0.146 g, 0.14 mmol) in ethanol (30 ml) was stirred in an atmosphere of H ₂ at room temperature. for 18 hours. The mixture was filtered through diatomaceous earth (Celite™) and the filtrate was concentrated in vacuo. The residue along with 10% Pd on carbon (0.146 g, 0.14 mmol) in CH3OH (60 ml) was stirred under H ₂ at room temperature. for 2 hours. The mixture was then filtered through diatomaceous earth (Celite™) and the filtrate was concentrated in vacuo to give the title compound (1.253 g, 94%) as a brown foam.

^1H NMR: 2.24 (3H, s), 2.51 (4H, m), 2.86 (4H, m), 3.72 (3H, s), 4.47 (2H, s), 6.54 (1H, s), 6.69 (1H, s), 7.30 (3H, s); m/z: ES ⁺ MH ⁺ 279.

Intermediate 73: 1-[2-Methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]guanidine.

Methanesulfonic acid (0.508 ml, 7.83 mmol) at room temperature. was added to a suspension of 2-methoxy-4-(4methylpiperazin-1-yl)-5-nitroaniline (Intermediate 14, 1.39 g, 5.22 mmol) in butan-1-ol (10 ml) and water (0. 5 ml). The resulting suspension was heated to 90°C and at this temperature a solution of cyanamide (0.439 g, 10.44 mmol) in water (0.22 ml) was added dropwise over a period of 1 min. The mixture was heated at 90°C for 0.5 h, then methanesulfonic acid (0.339 ml, 5.22 mmol) was added dropwise. At 10-minute intervals, additional cyanamide (0.219 g, 5.22 mmol), additional methanesulfonic acid (0.339 mL, 5.22 mmol), and additional cyanamide (0.329 g, 7.83 mmol) and additional methanesulfonic acid (0.339 ml, 5.22 mmol). The mixture was left to cool and diluted

- 55 046985 with 2-methyltetrahydrofuran (75 ml) and diethyl ether (75 ml). This solution was then made alkaline with 5 M NaOH to a pH of approximately 3. The resulting phases were separated and the aqueous solution was extracted with 2-methyltetrahydrofuran (3x50 ml). The combined organic solutions were washed with sat. brine and dried (MgSO ₄ ). The product precipitated on the drying agent, so after filtration the MgSO ₄ was washed with a hot mixture of CH ₂ Cl ₂ /CH ₃ OH 5:1 (5x100 ml) and the combined filtrates were concentrated in vacuo. The residue was dissolved in hot 2-propanol (80 ml), filtered hot and then concentrated in vacuo. The residue was dissolved in CH ₂ Cl ₂ (50 ml), filtered and the filtrate was concentrated in vacuo to give the title compound (1.49 g, 89%) as an orange foam. The product from the 2-propanol filtrate could only be obtained in amorphous form, so a 38 mg sample of the final product was crystallized from ethanol (approximately 100 µl) and collected by filtration, washed with ethanol and diethyl ether at -70°C and dried under vacuum to obtain the title compound (11 mg, 28%) as a yellow powder.

^1H NMR: 2.25 (3H, s), 2.44-2.49 (4H, m), 2.99-3.16 (4H, m), 3.91 (3H, s), 6.73 (1H, s), 7.38 (3H, s), 7.67 (1H, s); m/z: ES ⁺ MH ⁺ 309.

Intermediate 74. N-[5-Chloro-4-(III-indol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(4methylpiperazin-1-yl)benzene-1,3-diamine.

A mixture of 5-chloro-4-(III-indol-3-yl)-H-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]pyrimidin-2-amine (Intermediate 75, 350 mg, 0.71 mmol), iron (237 mg, 4.25 mmol) and NH ₄ Cl (26.5 mg, 0.50 mmol) were refluxed in ethanol (24 ml) and water (8 ml) for 2 hours. The mixture was then cooled and concentrated in vacuo to obtain a thick suspension. CH ₂ Cl ₂ (100 ml) and CH ₃ OH (10 ml) were added and the mixture was stirred for 0.25 h and then filtered. The filter cake was washed with additional CH ₂ Cl ₂ and CH3OH and the combined organic phase was dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 1-5% methanol ammonia in CH ₂ Cl ₂ gave the title compound (288 mg, 88%) as a yellow dry film.

1H NMR: 2.26 (3H, s), 2.47-2.56 (4H, m), 2.88 (4H, t), 3.70 (3H, s), 4.29 (2H, d), 6.72 (1H, s), 7.04 (1H , t), 7.14 (1H, s), 7.15-7.22 (1H, m), 7.46 (1H, d), 8.18 (1H, s), 8.35 (2H, d), 8.48 (1H, d), 11.81 ( 1H, s); m/z: ES ⁺ MH ⁺ 464.49.

Intermediate 75. 5-Chloro-4-(III-indol-3-yl)-H-[2-methoxy-4-(4-methylpiperazin-1yl)-5-nitrophenyl]pyrimidin-2-amine.

1-Methylpiperazine (492 μl, 4.44 mmol) was added to a suspension of 5-chloro-N-(4-fluoro-2-methoxy-5nitrophenyl)-4-(N-indol-3-yl)pyrimidin-2-amine ( Intermediate 76, 612 mg, 1.48 mmol). The mixture was heated at 120°C for 1 hour and then concentrated in vacuo. The residue was dissolved in CH ₂ Cl ₂ (25 ml) and washed with water (2x25 ml) and sat. brine (25 ml), then dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 1-10% CH ₃ OH in CH ₂ Cl ₂ gave the title compound as an orange gum. This resin was dissolved in ethanol (25 ml) and a solid precipitated. This solid was collected by filtration and washed with ethanol and diethyl ether to give the title compound (365 mg, 50%) as a yellow/orange solid.

1H NMR: 2.26 (3H, s), 2.47-2.55 (4H, m), 3.07-3.13 (4H, m), 3.93 (3H, s), 6.85 (1H, s), 6.99 (1H, t), 7.167 .22 (1H, m), 7.48 (1H, d), 8.26 (1H, d), 8.36 (1H, s), 8.42 (1H, d), 8.51 (1H, s), 8.54 (1H, s), 11.88 (1H, s); m/z: ES+MH+ 494.46.

Intermediate 76. 5-Chloro-H-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(III-indol-3yl)pyrimidin-2-amine.

A mixture of 3-(2,5-dichloropyrimidin-4-yl)-N-indole (Intermediate 11, 391 mg, 1.48 mmol), 4-fluoro-2-methoxy-5-nitroaniline (Intermediate 23, 289 mg , 1.55 mmol) and p-toluenesulfonic acid monohydrate (310 mg, 1.63 mmol) in 2-pentanol (25 ml) were heated at 125°C for 18 hours. The mixture was cooled and used in the next step without further purification; m/z: ES ⁺ MH ⁺ 414.12.

Intermediate 77. 4-Methoxy-N'-[5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-yl]-6(4-methylpiperazin-1-yl)benzene-1,3- diamine

No.[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-5-methyl-4-(1-methylindol-3yl)pyrimidin-2-amine mixture (Intermediate 78, 408 mg, 0.84 mmol), iron (280 mg, 5.02 mmol) and NH ₄ Cl (31.3 mg, 0.59 mmol) in ethanol (24 ml) and water (8.00 ml) were refluxed at for 3 hours. The mixture was cooled and concentrated in vacuo to obtain a thick suspension. CH ₂ Cl ₂ (100 ml) and CH3OH (10 ml) were added and the mixture was stirred for 0.25 h and then filtered. The filter cake was washed with additional CH ₂ Cl ₂ and CH3OH and the combined organic phase was dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 1-7% methanol ammonia in CH ₂ Cl ₂ gave the title compound (163 mg, 43%) as a yellow gum that crystallized on standing.

1H NMR (CDCl ₃ ): 2.36 (6H, s), 2.53 (3H, dd), 2.94 (4H, t), 3.69-3.79 (2H, m), 3.83 (3H, s), 3.86 (3H, s) ,

- 56 046985

6.69 (1H, s), 7.24-7.27 (1H, m), 7.29 (1H, dd), 7.33 (1H, dd), 7.36-7.40 (1H, m), 7.49 (1H, s), 7.58 (1H, s), 8.23 (1H, d), 8.26 (1H, s), 8.56 (1H, d); m/z: ES ⁺ MH ⁺ 458.37.

Intermediate 78. N[2-Methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-5-methyl4-(1-methylindol-3-yl)pyrimidin-2-amine.

1-Methylpiperazine (0.453 ml, 4.08 mmol) was added to the suspension of N(4-fluoro-2-methoxy-5nitrophenyl)-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate compound 79, 554 mg, 1.36 mmol) in 2,2,2-trifluoroethanol (10 ml). The mixture was heated under microwave conditions at 120°C for 1 hour. The mixture was then concentrated in vacuo and the residue was dissolved in CH ₂ Cl ₂ (50 ml). This solution was washed with water (2x50 ml) and sat. brine (50 ml), then dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 1-10% CH ₃ OH in CH ₂ Cl ₂ gave an orange resin. This resin was dissolved in ethanol (25 ml) and a solid precipitated. This solid was collected by filtration and washed with ethanol to give the title compound (413 mg, 62%) as a yellow/orange solid.

¹ H NMR: 2.25 (3H, s), 2.39 (3H, s), 2.45-2.54 (4H, m), 3.03-3.10 (4H, m), 3.91 (3H, s), 3.98 (3H, s), 6.86 (1H, s), 7.06 (1H, dd), 7.22-7.28 (1H, m), 7.51 (1H, d), 8.02 (1H, s), 8.07 (1H, s), 8.26-8.30 (1H, m), 8.38 (1H, d), 8.69 (1H, s); m/z: ES ⁺ MH ⁺ 488.29.

Intermediate 79. No. (4-Fluoro-2-methoxy-5-nitrophenyl)-5-methyl-4-(1-methylindol-3yl)pyrimidin-2-amine.

A mixture of 3-(2-chloro-5-methylpyrimidin-4-yl)-1-methyl-1H-indole (Intermediate 80, 350 mg, 1.36 mmol), 4-fluoro-2-methoxy-5-nitroaniline ( Intermediate 23, 265 mg, 1.43 mmol) and p-toluenesulfonic acid (284 mg, 1.49 mmol) in 2-pentanol (25 ml) were heated at 125°C for 24 hours. The mixture was then cooled and concentrated in vacuum. The resulting resin was used without further purification; m/z: ES ⁺ MH ⁺ 240.13.

Intermediate 80. 3-(2-Chloro-5-methylpyrimidin-4-yl)-III-indole

NaH (0.862 g, 21.54 mmol, 30% dispersion in mineral oil) at 0°C under N2 was added to 3(2-chloro-5-methylpyrimidin-4-yl)-N-indole (Intermediate 17, 5.0 g, 20.5 mmol) in THF (200 ml). The resulting solution was stirred at 0°C for 0.25 h. CH3I (1.347 ml, 21.54 mmol) was then added and the mixture was allowed to warm to room temperature. and stirred for 2 hours. The mixture was again cooled in an ice bath and additional NaH (0.862 g, 21.54 mmol, 30% dispersion in mineral oil) was added. The resulting suspension was stirred at 0°C for 10 minutes. CH ₃ I (1.347 mL, 21.54 mmol) was then added and the mixture was stirred for an additional 1 hour. The mixture was then diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic solution was washed with water (75 ml) and a solid formed at the solvent interface. The solid was collected by filtration and washed with water and EtOAc and then dried to give the title compound as a white solid. The phases were separated and the organic solution was further washed with water, which resulted in the formation of some more solid, which was also collected by filtration, washed with water and EtOAc and dried to obtain additional amount of the title compound as a white solid (total: 3.82 g , 72%). The organic solution was then washed with sat. brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was triturated with diethyl ether to give a solid, which was collected by filtration and dried in vacuo to give the title compound (0.883 g, 17%) as a beige solid; (total: 4.71 g, 89%).

^1H NMR: 2.48 (3H, s), 3.94 (3H, s), 7.24-7.36 (2H, m), 7.58 (1H, d), 8.25 (1H, s), 8.48 (1H, s), 8.57 ( 1H, d); m/z: ES ⁺ MH ⁺ 258.12.

Intermediate 81. >-(2-dimethylaminoethyl)-5-methoxy-H1-methyl-H ⁴ -[5-methyl-4-(1methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4 -triamine

A mixture of N-(2-dimethylaminoethyl)-2-methoxy-N'-methyl-H-[5-methyl-4-(1-methyl-indol-3yl)pyrimidin-2-yl]-5-nitrobenzene-1,4 -diamine (Intermediate 82, 202 mg, 0.41 mmol), iron (138 mg, 2.48 mmol) and NH4Cl (15.45 mg, 0.29 mmol) in ethanol (16 ml) and water (5, 33 ml) was refluxed for 3 hours. The mixture was then cooled and concentrated in vacuo to obtain a thick suspension. CH ₂ Cl ₂ (100 ml) and CH3OH (10 ml) were then added and the mixture was stirred for 0.25 h and then filtered. The filter cake was washed with additional CH ₂ Cl ₂ and CH3OH and the combined organic phase was dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 1-8% methanol ammonia in CH ₂ Cl ₂ provided the title compound (147 mg, 78%) as a yellow dry film; m/z: ES ⁺ MH ⁺ 460.36.

Intermediate 82. Na-(2-Dimethylaminoethyl)-2-methoxy-N'-methyl-H-[5-methyl-4-(1methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-1, 4-diamine

>,>,>-Trimethylethane-1,2-diamine (221 mg, 2.16 mmol) was added to a suspension of H-(4-fluoro-2methoxy-5-nitrophenyl)-5-methyl-4-(1-methylindol- 3-yl)pyrimidin-2-amine (Intermediate 79, 400 mg, 0.98 mmol) in DMA (4 ml). The mixture was heated under microwave conditions at 140°C for 0.5 hours. The mixture was then concentrated in vacuo and the residue was dissolved in EtOAc (100 ml). This

- 57 046985 the solution was washed with water (2x100 ml) and sat. brine (100 ml), dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 1-8% methanol ammonia in CH ₂ Cl ₂ provided the title compound (202 mg, 42%) as an orange dry film, m/z: ES ⁺ MH ⁺ 444.55.

Intermediate 83. 4-[(3R)-3-Dimethylaminopyrrolidin-1-yl]-6-methoxy-N-[5-methyl-4(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1 ,3-diamine

Mixture of N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-5-methyl-4-(1methylindol-3-yl)pyrimidin-2-amine (Intermediate 84, 325 mg, 0.65 mmol), iron (217 mg, 3.89 mmol) and NH ₄ Cl (24.26 mg, 0.45 mmol) in ethanol (16 ml) and water (5.33 ml) reflux for 3 hours. The mixture was then cooled and concentrated in vacuo to obtain a thick suspension. CH ₂ Cl ₂ (100 ml) and CH ₃ OH (10 ml) were then added and the mixture was stirred for 0.25 h and then filtered. The filter cake was washed with additional CH ₂ Cl ₂ and CH3OH and the combined organic phase was dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 1-8% methanol ammonia in CH2Cl2 gave the title compound (257 mg, 84%) as a yellow dry film.

^1H NMR: 1.76 (1H, td), 2.03 (1H, dt), 2.18 (6H, s), 2.37 (3H, s), 2.79-2.87 (1H, m), 2.88-2.97 (2H, m), 3.08-3.14 (1H, m), 3.18 (1H, dd), 3.73 (3H, s), 3.90 (3H, s), 4.19 (2H, s), 6.70 (1H, s), 7.13 (1H, t) , 7.25 (1H, t), 7.44 (1H, s), 7.51 (1H, d), 7.65 (1H, s), 8.04 (1H, s), 8.19 (1H, s), 8.46 (1H, d); m/z: ES ⁺ MH ⁺ 472.35.

Intermediate 84. N-{4-[(3R)-3-Dimethylaminopyrrolidin-1-yl]-2-methoxy-5nitrophenyl}-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine .

(3R)-N,N-Dimethylpyrrolidin-3-amine (255 mg, 2.24 mmol) was added to the suspension of 10(4-fluoro-2-methoxy-5-nitrophenyl)-5-methyl-4-(1-methylindole -3-yl)pyrimidin-2-amine (Intermediate 79, 414 mg, 1.02 mmol) in DMA (4 ml) and the mixture was heated under microwave conditions at 140°C for 0.5 h. The mixture was then concentrated in vacuo and the residue was dissolved in EtOAc (50 ml). Purification by ion exchange chromatography using an SCX column and eluting with 0.35 M methanol ammonia after concentrating the appropriate fractions in vacuo provided semi-purified material. Purification by FCC eluting with 1-8% CH3OH in CH ₂ Cl ₂ gave the title compound (330 mg, 65%) as an orange dry film.

1H NMR: 1.75-1.86 (1H, m), 2.13-2.19 (1H, m), 2.21 (6H, s), 2.37 (3H, s), 2.75 (1H, s), 3.10-3.20 (2H, m) , 3.21-3.27 (1H, m), 3.46 (1H, td), 3.90 (3H, s), 3.94 (3H, s), 6.56 (1H, s), 7.03 (1H, t), 7.21-7.26 (1H , m), 7.49 (1H, d), 7.94 (1H, s), 8.05 (1H, s), 8.23 (1H, s), 8.37 (1H, d), 8.39 (1H, s); m/z: ES ⁺ MH ⁺ 502.33.

Intermediate 85. N-[5-Chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-4-[(3R)-3dimethylaminopyrrolidin-1-yl]-6-methoxybenzene-1,3 -diamine

Mixture of 5-chloro-N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(1methylindol-3-yl)pyrimidin-2-amine (Intermediate 86, 747 mg, 1.43 mmol), iron (479 mg, 8.59 mmol) and NH ₄ Cl (53.6 mg, 1.00 mmol) in ethanol (48 ml) and water (16 ml) were boiled with reflux for 3 hours. The mixture was then cooled and concentrated in vacuo to obtain a thick suspension. CH ₂ Cl ₂ (100 ml) and CH ₃ OH (10 ml) were then added and the mixture was stirred for 0.25 h and then filtered. The filter cake was washed with additional CH ₂ Cl ₂ and MeOH and the combined organic phase was dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC (split into two batches) eluting with 1-9% methanolic ammonia in CH ₂ Cl ₂ gave the title compound (230 mg, 33%) as a yellow gum that crystallized on standing and (2 ^m batch) some more of the title compound (329 mg, 47%) as a yellow resin.

1H NMR (CDCl ₃ ): 1.87 (1H, ddt), 2.13 (1H, dtd), 2.29 (6H, s), 2.86 (1H, dq), 2.98-3.09 (2H, m), 3.20 (2H, dd) , 3.66 (2H, s), 3.84 (3H, s), 3.88 (3H, s), 6.70 (1H, s), 7.25-7.35 (2H, m), 7.38 (1H, dd), 7.61 (1H, s ), 8.10 (1H, s), 8.19 (1H, d), 8.32 (1H, s), 8.66 (1H, dd); m/z: ES ⁺ MH ⁺ 492.27.

Intermediate 86: 5-Chloro-N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5nitrophenyl}-4-(1-methylindol-3-yl)pyrimidin-2-amine .

(3R)-N,N-Dimethylpyrrolidin-3-amine (126 mg, 1.11 mmol) was added to a suspension of 5-chloro-Io(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindole -3-yl)pyrimidin-2-amine (Intermediate 87, 215 mg, 0.50 mmol) in DMA (5 ml) and the mixture was heated under microwave conditions at 140°C for 0.5 h. The mixture was then concentrated in vacuo and combined with the material from the reaction below for processing. (3R)-N,N-dimethylpyrrolidin-3-amine (276 mg, 2.42 mmol) was added to a suspension of 5-chloro-Yo(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindole-3 -yl)pyrimidin-2-amine (Intermediate 87, 470 mg, 1.10 mmol) in DMA (10 ml) and the mixture was heated under microwave conditions at 140°C for 0.5 h. The mixture was concentrated in vacuo and combined with the material from the first procedure described above for processing. The combined residues were dissolved in CH2Cl2 (100 ml) and the resulting solution was washed with water (2x100 ml) and sat. brine (100 ml) and then dried (MgSO4) and concentrated in vacuo. Resulting from FCC purification with 1-10% elution

- 58 046985

CH3OH in CH2C12 gave the title compound (747 mg, 89%) as an orange gum; m/z: ES ⁺ M+ 522.30.

Intermediate 87. 5-Chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3yl)pyrimidin-2-amine.

Mixture of 3-(2,5-dichloropyrimidin-4-yl)-1-methylindole (Intermediate 88, 1281 mg, 4.60 mmol), p-toluenesulfonic acid monohydrate (964 mg, 5.07 mmol) and 4-fluoro -2-methoxy-5nitroaniline (Intermediate 23, 900 mg, 4.84 mmol) in 2-pentanol (50 ml) was heated at 125°C for 18 hours. Upon cooling, a precipitate precipitated from the solution. The precipitate was collected by filtration, washed with CH3OH (10 mL) and diethyl ether (20 mL) and filter dried to give the title compound (1.42 g, 72%) as a tan solid which was used without further purification.

1H NMR: 3.91 (3H, s), 3.96 (3H, s), 7.05 (1H, t), 7.23-7.3 (1H, m), 7.39 (1H, d), 7.53 (1H, d), 8.33 (1H , d), 8.47 (1H, s), 8.58 (1H, s), 8.65 (1H, d), 8.76 (1H, s); m/z: ES ⁺ MH ⁺ 428.10.

Intermediate 88: 3-(2,5-Dichloropyrimidin-4-yl)-1-methylindole.

NaH (0.795 g, 19.88 mmol) at 0°C under N2 was added to 3-(2,5-dichloropyrimidin-4-yl)-III-indole (Intermediate 11, 5.0 g, 18.9 mmol) in THF (200 ml) and the mixture was stirred at 0°C for 0.25 h. CH ₃ I (1.243 ml, 19.88 mmol) was then added and the mixture was allowed to warm to room temperature. and stirred for 1 hour. The mixture was again cooled in an ice bath and additional NaH (0.795 g, 19.88 mmol) was added. The suspension was stirred at 0°C for 10 minutes, then CH3I (1.243 ml, 19.88 mmol) was added and the mixture was stirred for 1 hour. The mixture was then diluted with water (100 ml), which resulted in the formation of some solid. The solid was collected by filtration and washed with water and EtOAc and then dried to give the title compound (3.67 g, 70%) as a beige solid. The organic solution was further washed with water and sat. brine and then dried (MgSO ₄ ) and concentrated in vacuo. Trituration of the residue with diethyl ether gave a solid, which was collected by filtration and dried in vacuo to give the title compound (477 mg, 9%) as a brown solid. This material was only 71% pure, so it was stored separately from the earlier batch.

1H NMR: 3.97 (3H, s), 7.34 (2H, dtd), 7.59-7.65 (1H, m), 8.56 (1H, dd), 8.73 (1H, s), 8.79 (1H, s); m/z: ES ⁺ MH ⁺ 278.06.

Intermediate 89 2-({5-Amino-4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxyphenyl}amino)-4-(1-methylindol-3-yl)-pyrimidin-5 -carbonitrile.

A mixture of N-[5-chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-4-[(3R)-3-dimethylaminopyrrolidin-1yl]-6-methoxybenzene-1,3-diamine ( Intermediate 85, 324 mg, 0.66 mmol), zinc powder (4.3 mg, 0.07 mmol), tris-(dibenzylideneacetone)-dipalladium(0) (60.3 mg, 0.07 mmol), dicyclohexyl (2',4',6'-triisopropylbiphenyl-2-yl)phosphine (XPhos, 62.8 mg, 0.13 mmol) and dicyanozinc (46.4 mg, 0.40 mmol) were placed in a reaction tube under N2 and then degassed DMA (1.75 ml) was added. The resulting suspension was heated to 95°C and stirred for 2 hours. The mixture was then diluted with EtOAc and washed 5 times with water and then with brine. The solution was dried (MgSO ₄ ) and concentrated in vacuo. The residue was dissolved in CH3OH and allowed to flow through a PL-Thiol MP SPE stratospheres SPE cartridge (available from Polymer Laboratories) under gravity. The resulting solution was concentrated in vacuo and the resulting residue was triturated with diethyl ether. The resulting solid was collected by filtration and washed with diethyl ether to give the title compound (184 mg, 58%) as a yellow solid.

1H NMR (100°C): 1.8-1.88 (1H, m), 2.03-2.11 (1H, m), 2.24 (6H, s), 2.92-2.99 (1H, m), 3.01-3.05 (1H, m) , 3.06-3.11 (1H, m), 3.20 (2H, ddd), 3.69 (3H, s), 3.90 (3H, s), 4.17 (2H, br s), 6.73 (1H, s), 7.04 (1H, s), 7.10 (1H, t), 7.26 (1H, t), 7.50 (1H, d), 8.31 (1H, d), 8.42 (1H, s), 8.60 (1H, s), 8.62 (1H, s ); m/z: ES ⁺ MH ⁺ 483.31.

Intermediate 90. 2-{[5-Amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4(1-methylindol-3-yl)pyrimidine-5-carbonitrile.

Mixture of N-[5-chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(4-methylpiperazin-1yl)benzene-1,3-diamine (Intermediate 91 , 344 mg, 0.72 mmol), zinc powder (4.71 mg, 0.07 mmol), tris-(dibenzylideneacetone) dipalladium(0) (65.9 mg, 0.07 mmol), dicyclohexyl(2', 4',6'triisopropylbiphenyl-2-yl)phosphine ('XPhos', 68.6 mg, 0.14 mmol) and dicyanozinc (50.7 mg, 0.43 mmol) were placed in a reaction tube under No. ₂ and then added degassed DMA (1.91 ml). The resulting suspension was stirred at 95°C for 2 hours. The mixture was then diluted with EtOAc and washed 5 times with water and then with brine. The solution was then dried (MgSO4) and concentrated in vacuo. The residue was dissolved in CH3OH and allowed to flow through a stratospheres SPE PL-Thiol MP SPE cartridge (available from Polymer Laboratories) by gravity. The resulting solution was concentrated in vacuo and the resulting residue was triturated with diethyl ether. The resulting solid was collected by filtration and washed with diethyl ether to give the title compound (208 mg, 62%) as a yellow solid.

1H NMR: 2.28 (3H, s), 2.51-2.58 (4H, m), 2.89-2.95 (4H, m), 3.69 (3H, s), 3.91 (3H, s), 4.23 (2H, br s), 6.75 (1H, s), 7.08 (1H, s), 7.09-7.12 (1H, m), 7.26 (1H, ddd), 7.50 (1H, d), 8.31 (1H, d), 8.43 (1H, s) , 8.61 (1H,

- 59 046985

s), 8.64 (1H, s); m/z: ES ⁺ MH ⁺ 469.33.

Intermediate 91. Na-[5-Chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(4methylpiperazin-1-yl)benzene-1,3-diamine.

Mixture of 5-chloro-N[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-4-(1-methylindol-3yl)pyrimidin-2-amine (Intermediate 92, 750 mg, 1.48 mmol), iron (495 mg, 8.86 mmol) and NH4Cl (55.3 mg, 1.03 mmol) in ethanol (12 ml) and water (4 ml) were refluxed for 4 hours. Purification by ion exchange chromatography using an SCX column and eluting with 7 M methanol ammonia provided a partially purified material which was concentrated in vacuo on silica. As a result of purification by FCC eluting with 0-4% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (367 mg, 52%) as a yellow solid. The crude fractions containing the title product were concentrated in vacuo and the resulting residue was triturated with CH ₂ C _{1 2} /diethyl ether to obtain additional amount of the title compound (230 mg, 33%) as a yellow solid. Total: 597 mg, 85%.

^1H NMR ( _CDCl3 ): 2.37 (3H, s), 2.56 (4H, br s), 2.95 (4H, br t), 3.75 (2H, br s), 3.84 (3H, s), 3.90 (3H, s), 6.70 (1H, s), 7.27-7.36 (2H, m), 7.38-7.42 (1H, m), 7.63 (1H, s), 8.13 (1H, s), 8.21 (1H, s), 8.33 (1H, s), 8.638.69 (1H, m); m/z: ES+MH+ 478.55.

Intermediate 92. 5-Chloro-N[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-4(1-methylindol-3-yl)pyrimidin-2-amine.

1-Methylpiperazine (0.50 ml, 4.51 mmol) was added to a suspension of 5-chloro-N(4-fluoro-2-methoxy-5nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 87, 750 mg, 1.75 mmol) in 2,2,2-trifluoroethanol (15 ml) and the mixture was heated under microwave conditions at 120°C for 1 hour and then at 140°C for 0. 5 hours. The mixture was then concentrated in vacuo and the residue was dissolved in EtOAc (100 ml). This organic solution was washed with sat. NaHCO ₃ (100 ml), water (2x100 ml) and then brine (100 ml). The solution was then dried (MgSO ₄ ) and concentrated in vacuo on silica. Purification by FCC eluting with 0-4% CH3OH in CH2Cl2 gave the title compound (772 mg, 87%) as an orange solid.

^1H NMR ( _CDCl3 ): 2.37 (3H, s), 2.59-2.65 (4H, m), 3.07-3.14 (4H, m), 3.90 (3H, s), 3.99 (3H, s), 6.63 (1H , s), 7.25-7.3 (1H, m) partially hidden by the chloroform peak, 7.31-7.36 (1H, m), 7.39 (1H, d), 7.56 (1H, s), 8.22 (1H, s), 8.39 (1H , s), 8.47 (1H, d), 9.18 (1H, s); m/z: ES+MH+ 508.19.

Intermediate 93. N-[5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxybenzene-1 ,3-diamine

A mixture of 5-chloro-N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(1Hindol-3-yl)pyrimidin-2-amine ( Intermediate 94, 350 mg, 0.69 mmol), iron (231 mg, 4.13 mmol) and NH4Cl (27.6 mg, 0.52 mmol) in ethanol (15 ml) and water (5 ml) were boiled with reflux for 1.5 hours. The mixture was then cooled and concentrated in vacuo. The residue was triturated with 10% CH3OH in CH ₂ Cl ₂ (15 ml) for 0.25 h and then filtered. The residue was triturated again with 10% CH3OH in CH ₂ Cl ₂ (15 ml) and then filtered. The combined filtrates were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 3% CH ₃ OH in CH ₂ Cl ₂ and then 2-5% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (261 mg, 79%) as a yellow foam.

1H NMR: 1.73-1.86 (1H, m), 1.99-2.12 (1H, m), 2.20 (6H, s), 2.81-2.91 (1H, m), 2.97 (2H, ddd), 3.12-3.26 (2H, m), 3.69 (3H, s), 4.20 (2H, d), 6.71 (1H, s), 7.03 (1H, t), 7.07 (1H, s), 7.14-7.22 (1H, m), 7.46 (1H , d), 8.18 (1H, s), 8.3-8.39 (2H, m), 8.48 (1H, s), 11.81 (1H, s); yes/z: ES ⁺ MH ⁺ 478.5.

Intermediate 94. 5-Chloro-N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5nitrophenyl}-4-(1H-indol-3-yl)pyrimidin-2-amine .

U)-(+)-3-(Dimethylamino)pyrrolidine (0.111 ml, 0.87 mmol) was added to the suspension of 5-χλορ-Ν-(4fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol- 3-yl)pyrimidin-2-amine (Intermediate 76, 300 mg, 0.73 mmol) and DIPEA (0.151 ml, 0.87 mmol) in DMA (3 ml) and the mixture was heated at 140°C under microwave conditions for 0.5 h. The mixture was then diluted with CH3OH and absorbed onto an SCX column. The column was washed with CH3OH and eluted with a 1:1 mixture of methanolic ammonia and CH ₂ Cl ₂ . The appropriate fractions were concentrated and further purified by FCC eluting with 1.5% 7N. methanolic ammonia in CH ₂ Cl ₂ to give the title compound (353 mg, 96%) as an orange foam.

1H NMR: 1.78-1.91 (1H, m), 2.16-2.27 (7H, m), 2.70-2.85 (1H, m), 3.12-3.29 (3H, m), 3.41-3.55 (1H, m), 3.89 ( 3Н, s), 6.57 (1H, s), 6.95 (1H, t), 7.17 (1H, t), 7.46 (1H, d), 8.09 (1H, s), 8.24 (1H, br s), 8.37 ( 1H, s), 8.50 (1H, d), 8.54 (1H, s), 11.88 (1H, s); m/z: ES'MH' 508.5.

Intermediate 95. A-[5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]A-(2-dimethylamino-ethyl)-5-methoxy->-methylbenzene-1,2, 4-triamine

Mixture of N[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-N-(2-dimethylaminoethyl)-2-methoxy-N-methyl5-nitrobenzene-1,4-diamine (Intermediate compound 96, 350 mg, 0.71 mmol), iron (236 mg, 4.23 mmol) and NH ₄ Cl (28.3 mg, 0.53 mmol) in ethanol (15 ml) and water (5 ml) were boiled with reverse holo

- 60 046985 for 1.5 hours. The mixture was then cooled and concentrated in vacuo. The residue was triturated with 10% CH3OH in CH2Cl2 (15 ml) for 0.25 h and then filtered. The residue was triturated again with 10% CH3OH in CH ₂ Cl ₂ (15 ml) and then filtered. The combined filtrates were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 5% CH3OH in CH ₂ Cl ₂ and then 2-5% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (159 mg, 48%) as a yellow foam.

1H NMR: 2.18 (6H, s), 2.38 (2H, t), 2.66 (3H, s), 2.91 (2H, t), 3.68 (3H, s), 4.54 (2H, s), 6.77 (1H, s ), 6.997.10 (2H, m), 7.12-7.22 (1H, m), 7.46 (1H, d), 8.25 (1H, s), 8.30-8.40 (2H, m), 8.49 (1H, d), 11.85 (1H, s); m/z: ES+MH+ 466.6.

Intermediate 96. N-[5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-N'-(2-dimethylaminoethyl)-2-methoxy-N-methyl-5-nitrobenzene- 1,4-Diamine

NNN'-trimethylethylenediamine (0.113 ml, 0.87 mmol) was added to a suspension of 5-chloro-N-(4-fluoro-2methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 76, 300 mg, 0.73 mmol) and DIPEA (0.151 mL, 0.87 mmol) in DMA (3 mL) and the mixture was heated at 140°C under microwave conditions for 0.5 h. The mixture was then heated diluted with CH ₃ OH and absorbed on an SCX column. The column was washed with _CH3OH and eluted with a 1:1 mixture of methanolic ammonia and CH2C12. The appropriate fractions were concentrated and purified by FCC eluting with 2% 7N. methanolic ammonia in CH2C12 to give the title compound (354 mg, 98%) as an orange foam.

1H NMR: 2.16 (6H, s), 2.52 (2H+DMSO, m), 2.87 (3H, s), 3.30 (2H, t), 3.89 (3H, s), 6.84 (1H, s), 6.97 (1H , t), 7.13-7.23 (1H, m), 7.46 (1H, d), 8.16 (1H, s), 8.23 (1H, br d), 8.40 (1H, s), 8.51 (1H, d), 8.55 (1H, s), 11.89 (1H, s); m/z: ES ⁺ MH ⁺ 469.5.

Intermediate 97. Y-[5-Chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-N-(2-dimethylaminoethyl)-5-methoxy-N-methylbenzene-1,2, 4-triamine

A mixture of N[5-chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-Nam-(2-dimethylamino-ethyl)-2-methoxy-Nmethyl-5-nitrobenzene-1,4- diamine (Intermediate 98, 553 mg, 1.08 mmol), iron (363 mg, 6.51 mmol) and NH ₄ Cl (43.5 mg, 0.81 mmol) in ethanol (23 ml) and water (7 .67 ml) was refluxed for 1.5 hours. The mixture was then cooled and concentrated in vacuo. The resulting residue was dissolved in CH ₂ Cl ₂ (100 ml) and CH ₃ OH (10 ml) and the mixture was stirred for 0.25 h and then filtered. The filter cake was washed with additional CH ₂ Cl ₂ and CH ₃ OH and the combined organic phase was dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 0-5% methanol ammonia in CH2C12 provided a solid. This solid was dissolved in diethyl ether and a small amount of brown precipitate was removed by filtration. The filtrate was concentrated in vacuo to give the title compound (409 mg, 79%) as a brown glass.

1H NMR (CDC13): 2.26 (6H, s), 2.38-2.43 (2H, m), 2.68 (3H, s), 2.94-2.98 (2H, m), 3.84 (3H, s), 3.91 (3H, s ), 6.71 (1H, s), 7.26-7.36 (2H, m), 7.40 (1H, d), 7.63 (1H, s), 8.09 (1H, s), 8.21 (1H, s), 8.33 (1H, s), 8.67 (1H, d); m/z: ES ⁺ MH ⁺ 480.32.

Intermediate 98. N[5-Chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-N-(2-dimethylaminoethyl)-2-methoxy-N-methyl-5-nitrobenzene-1, 4-diamine

N,N,U-trimethylethane-1,2-diamine (0.189 ml, 1.49 mmol) was added to the suspension of 5-chloro-Na(4-fluoro2-methoxy-5-nitrophenyl)-4-(1-methylindole-3 -yl)pyrimidin-2-amine (Intermediate 87, 700 mg, 1.24 mmol) and DIPEA (0.431 ml, 2.48 mmol) in DMA (5 ml). The mixture was then heated under microwave conditions at 140°C for 0.5 hours. The mixture was diluted with CH3OH and absorbed onto an SCX column. The column was washed with CH3OH and eluted with approximately 1 M methanolic ammonia. Appropriate fractions were concentrated and further purified by FCC eluting with 0-5% methanolic ammonia in CH2Cl2 to give the title compound (561 mg, 89%) as an orange oil.

1H NMR (CDC13): 2.26 (6H, s), 2.53-2.58 (2H, m), 2.88 (3H, s), 3.24-3.28 (2H, m), 3.91 (3H, s), 3.98 (3H, s ), 6.68 (1H, s), 7.26-7.3 (1H, m), 7.31-7.4 (2H, m), 7.50 (1H, s), 8.23 (1H, s), 8.39 (1H, s), 8.47 ( 1H, d), 9.07 (1H, s); m/z: ES+MH+ 510.27.

Intermediate 99. 2-{[5-Amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4(1H-indol-3-yl)pyrimidin-5-carbonitrile.

I-|5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3diamine (Intermediate 74, 268 mg, 0.58 mmol), zinc powder (3.78 mg, 0.06 mmol), tris(dibenzylideneacetone)diyalladium(0) (52.9 mg, 0.06 mmol), dicyclohexyl(2',4',6'-triisopropylbiphenyl2-yl)phosphine (XPhos, 55.1 mg, 0.12 mmol) and dicyanozinc (40.7 mg, 0.35 mmol) were placed in a flask under N2 and then degassed DMA (3 ml) was added. The resulting suspension was stirred for 3 hours at 95°C. The mixture was then diluted with EtOAc and washed 5 times with water and then brine. The solution was then dried (MgSO4) and concentrated in vacuo. The resulting residue was triturated with diethyl ether, and the resulting solid was collected by filtration and washed with diethyl ether to obtain the crude product. This crude material was dissolved in a mixture of CH ₂ Cl ₂ /CH ₃ OH and conc.

- 61 046985 were dug in a vacuum on silicon dioxide. As a result of purification by FCC eluting with 1.5-8% 7N. methanolic ammonia in CH2Cl2 gave a solid which was washed with CH3OH (0.2 mL) to give the title compound (48 mg, 18%) as a beige crystalline solid.

^1H NMR: 2.26 (3H, s), 2.53 (4H, m), 2.91 (4H, s), 3.65 (3H, s), 4.38 (2H, d), 6.74 (1H, s), 6.85 (1H, s), 6.99 (1H, s), 7.19 (1H, s), 7.48 (1H, d), 8.01 (1H, s), 8.52 (1H, s), 8.65 (1H, s), 9.21 (1H, s ), 11.97 (1H, s); m/z: ES+ MH 455.

Intermediate 100. A-^-Dimethylaminoethyl^-methoxy-A-methyl-N^-P-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine.

A mixture of H'-(2-dimethylaminoethyl)-2-methoxy-H'-methyl-H-[4-(1-methylindol-3-yl)pyrimidin-2-yl]-5nitrobenzene-1,4-diamine (Intermediate 101, 220 mg, 0.46 mmol), iron (155 mg, 2.78 mmol) and NH4C1 (17.32 mg, 0.32 mmol) in ethanol (12 ml) and water (4 ml) were refluxed for 2 hours. The crude mixture was purified by ion exchange chromatography using an SCX column. The target product was eluted from the column using 7 M methanolic ammonia, and the appropriate fractions were combined and concentrated in vacuo on silica. As a result of purification by FCC eluting with 0-5% 7N. methanolic ammonia in CH2Cl2 gave the title compound (175 mg, 85%) as a beige foam.

^1H NMR: 2.17 (6H, s), 2.36 (2H, t), 2.63 (3H, s), 2.88 (2H, t), 3.74 (3H, s), 3.88 (3H, s), 4.58 (2H, br s), 6.76 (1H, s), 7.12-7.19 (2H, m), 7.21-7.27 (1H, m), 7.48 (1H, s), 7.51 (1H, d), 7.78 (1H, s), 8.27 (1H, d), 8.30 (1H, s), 8.42 (1H, d); m/z: ES ⁺ MH ⁺ 446.32.

Intermediate 101. H'-(2-Dimethylaminoethyl)-2-methoxy-H'-methyl-H-[4-(1-methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-1,4 -diamine

^H1 , ^H1 ,H2-Trimethylethane-1,2-diamine (80 mg, 0.79 mmol) was added to the suspension of H-(4-fluoro-2methoxy-5-nitrophenyl)-4-(1-methylindole-3- yl)pyrimidin-2-amine (Intermediate 129 (which can be prepared as described for Intermediate 87); 350 mg, 0.79 mmol) and DIPEA (0.342 ml, 1.97 mmol) in 2,2,2 -trifluoroethanol (5 ml). The mixture was heated under microwave conditions at 140°C for 1 hour. The cooled reaction mixture was purified by ion exchange chromatography using an SCX column. The target product was eluted from the column using 7 M methanolic ammonia, and the appropriate fractions were combined and concentrated in vacuo on silica. As a result of purification by FCC eluting with 0-4% 7N. methanolic ammonia in CH2Cl2 gave the title compound (230 mg, 62%) as an orange solid.

^1H NMR: 2.16 (6H, s), 2.45-2.49 (2H, t, hidden by DMSO peak), 2.86 (3H, s), 3.26 (2H, t), 3.87 (3H, s), 3.95 (3H, s ), 6.85 (1H, s), 7.11 (1H, t), 7.21 (1H, d), 7.25 (1H, t), 7.52 (1H, d), 8.10 (1H, s), 8.31 (1H, d) , 8.33 (1H, s), 8.36 (1H, d), 8.62 (1H, s); m/z: ES ⁺ MH+ 476.40.

Intermediate 102. 2-{[5-Amino-4-(2-dimethylaminoethylmethylamino)-2-methoxyphenyl]amino}-4-(1-methylindol-3-yl)pyrimidin-5-carbonitrile.

H4-[5-Chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl] ^-N1- (2-dimethylaminoethyl)-5-methoxy- ^H1 -methylbenzene-1,2,4-triamine (Intermediate 97, 250 mg, 0.52 mmol), zinc (3.41 mg, 0.05 mmol), tris-(dibenzylideneacetone)dipalladium(0) (47.7 mg, 0.05 mmol), dicyclohexyl( 2',4',6'-triisopropylbiphenyl-2-yl)phosphine ('XPhos', 49.7 mg, 0.10 mmol) and dicyanozinc (36.7 mg, 0.31 mmol) were placed in a reaction tube under N2 and then degassed DMA (1.38 ml) was added. The resulting suspension was stirred for 3.5 hours at 95°C. The mixture was then diluted with EtOAc and washed 5 times with water and then brine. The solution was then dried (MgSO ₄ ) and concentrated in vacuo. The residue was dissolved in

- 62 046985 the CH3OH/CH2C12 mixture and solution were allowed to flow through a SPEPL-Thiol MP SPE stratospheres cartridge (available from Polymer Laboratories) by gravity. The resulting solution was concentrated in vacuo and the residue was triturated with diethyl ether. The resulting solid was collected by filtration and washed with diethyl ether to obtain the title compound (80 mg) as a yellow solid. Aqueous working solutions were purified by ion exchange chromatography using an SCX column. The target product was eluted from the column using 7 M methanolic ammonia and the pure fractions were concentrated in vacuo to give a brown oil (126 mg). Purification by FCC eluting with 0-5% methanol ammonia in CH ₂ Cl ₂ gave the title compound (94 mg) as a yellow solid. Both batches of product were combined to give product (174 mg, 71%) as a yellow solid; m/z: ES ⁺ MH ⁺ 471.33.

Intermediate 103: 4-[(3R)-3-Dimethylaminopyrrolidin-1-yl]-6-methoxy-N-[4-(1methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine.

Mixture of (N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(1-methylindol-3yl)pyrimidin-2-amine (Intermediate 104, 360 mg, 0.74 mmol), iron (247 mg, 4.43 mmol) and NH ₄ Cl (27.6 mg, 0.52 mmol) in ethanol (12 ml) and water (4 ml) were refluxed for 2 hours. The crude mixture was purified by ion exchange chromatography using an SCX column. The target product was eluted from the column using 7 M methanol ammonia and the appropriate fractions were combined and concentrated in vacuo on silica. Purification by FCC eluting 0-5. % 7N methanol ammonia in CH ₂ Cl ₂ gave the title compound (280 mg, 83%) as a beige foam.

^1H NMR: 1.69-1.83 (1H, m), 1.97-2.10 (1H, m), 2.18 (6H, s), 2.78-2.87 (1H, m), 2.88-2.98 (2H, m), 3.11 (1H , dd), 3.15-3.22 (1H, m), 3.74 (3H, s), 3.87 (3H, s), 4.29 (2H, br s), 6.70 (1H, s), 7.1-7.19 (2H, m) , 7.21-7.28 (1H, m), 7.46 (1H, s), 7.51 (1H, d), 7.78 (1H, s), 8.25 (1H, d), 8.29 (1H, s), 8.43 (1H, d ); m/z: ES ⁺ MH ⁺ 458.35.

Intermediate 104. N-[4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine.

(3R)-N,N-Dimethylpyrrolidin-3-amine (107 mg, 0.94 mmol) was added to the suspension of Na(4-fluoro-2methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidine -2-amine (Intermediate 129 (which can be prepared as described for Intermediate 87), 0.372 mL, 2.13 mmol) in 2,2,2-trifluoroethanol (5 mL) and the mixture was heated under microwave conditions at 140°C for 1 hour. The cooled mixture was purified by ion exchange chromatography using an SCX column. The target product was eluted from the column using 7 M methanolic ammonia, and the appropriate fractions were combined and concentrated in vacuo on silica. As a result of purification by FCC eluting with 0-4% 7N. methanolic ammonia in CH2Cl2 gave the title compound (364 mg, 87%) as an orange solid.

1H NMR: 1.74-1.87 (1H, m), 2.11-2.22 (1H, m), 2.21 (6H, s), 2.70-2.81 (1H, m), 3.10-3.21 (2H, m), 3.213.28 ( 1H, m), 3.47 (1H, td), 3.87 (3H, s), 3.95 (3H, s), 6.56 (1H, s), 7.10 (1H, t), 7.18 (1H, d), 7.21-7.27 (1H, m), 7.51 (1H, d), 8.07 (1H, s), 8.29 (1H, d), 8.32 (1H, s), 8.36 (1H, d), 8.54 (1H, s); m/z: ES+MH+ 488.31.

Intermediate 105. ^-(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-5methoxy-NAmethyl-HA^-morpholine-ylethyl^enzoleDD-triamine.

A solution of NH ₄ Cl (28.1 mg, 0.53 mmol) in water (13.00 ml) was added in one portion to the stirred mixture of Na(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidine -2-yl)-2-methoxy-N'-methyl-H'-(2-morpholine-4ylethyl)-5-nitrobenzene-1,4-diamine (Intermediate 106, 426 mg, 0.75 mmol) and iron (251 mg, 4.50 mmol) in ethanol (39 ml). The resulting mixture was stirred at reflux for 2 hours. Additional iron (251 mg, 4.50 mmol) and NH ₄ Cl (28.1 mg, 0.53 mmol) were added and the mixture was stirred at reflux at for an additional 0.5 hours. The mixture was concentrated in vacuo and the residue was mixed with DMF (5 ml) and then purified by ion exchange chromatography using an SCX column. The target product was eluted from the column using 7 M methanol ammonia in CH2Cl2, and the appropriate fractions were combined and concentrated in vacuo. Purification by FCC eluting with 1.5-7% 2M methanol ammonia in CH ₂ Cl ₂ gave the title compound (304 mg, 80%) as a yellow foam.

1H NMR: 2.43 (4H, m), 2.45 (2H, t), 2.68 (3H, s), 2.93 (2H, t), 3.51-3.61 (4H, m), 3.66 (3H, s), 4.73 (2H , s), 6.77 (1H, s), 6.90 (1H, s), 7.12 (1H, m), 7.34 (1H, m), 8.37 (1H, s), 8.43 (1H, d), 8.49 (1H, s), 8.84 (1H, d), 8.95 (1H, s); m/z: ES+MH+ 509.

Intermediate 106. N(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-2methoxy-H'-methyl-H'-(2-morpholin-4-ylethyl) -5-nitrobenzene-1,4-diamine.

5-Chloro-H-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 20, 311 mg, 0.75 mmol), Nmethyl-2-morpholinoethanamine (130 mg, 0.90 mmol) and DIPEA (0.157 mL, 0.90 mmol) were dissolved in DMA (3 mL) and sealed in a microwavable tube. The mixture was heated under microwave conditions to 140°C for 0.75 h, then cooled to room temperature. The mixture was then diluted with CH ₃ OH and purified by ion exchange chromatography using an SCX column and eluting 1:1 with 7N. methanol ammonia in CH ₂ Cl ₂ . The appropriate fractions were combined and concentrated in vacuo to give the following:

- 63 046985 compound (429 mg, 106%) as an orange solid, which was used without further purification.

^1H NMR: 2.36 (4H, s), 2.54 (2H, m), 2.89 (3H, s), 3.34 (2H, m), 3.49 (4H, m), 3.91 (3H, s), 6.81 (1H, s), 7.15 (1H, m), 7.35 (1H, t), 8.16 (1H, s), 8.45 (2H, m), 8.76 (1H, s), 8.86 (1H, d), 8.96 (1H, s ); m/z: ES+MH+ 539.

Intermediate 107. M ^| -(5-Chloro-4-pyrazolo[1.5-a|pyridin-3-ylpyrimidin-2-yl)-5methoxy-N ¹ -methyl-N-[2-(4-methylpiperazin-1 -yl)ethyl] benzene- 1,2,4-triamine.

Mixture of N(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-2-methoxy-H'-methyl-H'-[2-(4methylpiperazin-1-yl) ethyl]-5-nitrobenzene-1,4-diamine (0.182 g, 0.33 mmol), iron (0.110 g, 1.98 mmol) and NH4C1 (0.012 g, 0.23 mmol) in EtOH (10 ml) and water (3.33 ml) was refluxed for 1.5 hours. The mixture was then cooled to room temperature, filtered and concentrated in vacuo. Purification by ion exchange chromatography using an SCX column eluting with 1 M methanol ammonia and concentrating the appropriate fractions gave a brown gum (162 mg). Further purification by FCC eluting with 27% 1M methanol ammonia in CH ₂ Cl ₂ gave the title compound (0.148 g, 86%) as a yellow gum.

^1H NMR (CDC13): 2.28 (3H, s), 2.32-2.63 (10H, m), 2.70 (3H, s), 2.98 (2H, t), 3.84 (3H, s), 4.05 (2H, d) , 6.71 (1H, s), 6.95 (1H, td), 7.38 (1H, ddd), 7.52 (1H, d), 7.88 (1H, s), 8.36 (1H, s), 8.57 (1H, d), 8.65 (1H, d), 8.93 (1H, s); m/z: ES+MH ^4,522.57 .

Intermediate 108. N(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-2methoxy-N'-methyl-H'-[2-(4-methylpiperazin-1 -yl)ethyl]-5-nitrobenzene-1,4-diamine.

DIPEA (0.105 ml, 0.60 mmol) was added to a mixture of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4pyrazolo[1,5-a|pyridin-3-ylpyrimidin-2-amine (Intermediate 20, 0.207 g, 0.5 mmol) and Nmethyl-2-(4-methylpiperazin-1-yl)ethanamine (Intermediate 109, 0.079 g, 0.50 mmol) in DMA (5 ml). The mixture was heated under microwave conditions at 140°C for 3 hours. An additional portion of Nmethyl-2-(4-methylpiperazin-1-yl)ethanamine (8 mg, 0.05 mmol) was added and the mixture was heated under microwave conditions at 140°C for 1 additional hour, then cooled to room temperature. The mixture was then concentrated in vacuo and the residue was dissolved in CH ₃ OH. Purification by ion exchange chromatography using an SCX column eluting with 1 M methanol ammonia and concentrating the appropriate fractions in vacuo provided the crude material. Further purification by FCC eluting with 2-8% CH3OH in CH2C12 gave the title compound (0.186 g, 67%) as an orange foam.

^1H NMR (CDC13): 2.26 (3H, s), 2.32-2.45 (4H, m), 2.45-2.57 (4H, m), 2.61 (2H, t), 2.89 (3H, s), 3.29 (2H, t), 3.98 (3H, s), 6.65 (1H, s), 6.93-7.00 (1H, m), 7.38 (1H, ddd), 7.44 (1H, s), 8.40 (1H, s), 8.49 (1H , d), 8.55 (1H, d), 8.91 (2H, d); m/z: ES+MH ^4,552.59 .

Intermediate 109. No. Methyl-2-(4-methylpiperazin-1-yl)ethanamine.

Ethyl carbonochloridate (8.14 mL, 85.14 mmol) was added dropwise to Nmethyl-2-piperazin-1ylethanamine (5.0 g, 38.7 mmol) and triethylamine (12.95 mL, 92.88 mmol) in THE (40 ml) at 0°C for a period of 10 min under N2. The resulting mixture was left to warm to room temperature. and stirred for 2 hours. The resulting white suspension was filtered and washed using THE (2x20 ml). The filtrate was concentrated in vacuo and the resulting residue was dissolved in EtOAc (75 ml). This solution was washed with sat. Na ₂ CO ₃ (50 ml). The aqueous wash solution was then extracted with EtOAc (50 ml). The combined organic solutions were dried (MgSO ₄ ) and concentrated in vacuo to give the crude intermediate (10.55 g). This compound was dissolved in THE (60 ml) and cooled to 0°C. Al1H4 (101 ml, 100.6 mmol, 1 M in THE) was added dropwise under N2. The resulting mixture was stirred at reflux overnight, then cooled to 0°C and successively treated dropwise with water (3.8 ml), 15% aq. No. YuN (3.8 ml) and water (11.4 ml) with rapid stirring. Diatomaceous earth (Celite™) and MgSO ₄ were added and the mixture was filtered, washed with EtOAc and the filtrate concentrated in vacuo to give a colorless oil (3.35 g). The filter cake was washed with EtOAc (100 ml), heated to 70°C and then filtered. The filtrate was concentrated in vacuo to obtain an additional batch (1.023 g) of the title compound. Total: 4.37 g, 72%.

^1H NMR (CDC13): 2.28 (3H, s), 2.33-2.6 (13H, m), 2.67 (2H, t).

Intermediate 110. 4-Methoxy-N'-[4-(1-methylindol-3-yl)pyrimidin-2-yl]-6-(4methylpiperazin-1-yl)benzene-1,3-diamine.

No.[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin2-amine mixture (Intermediate 111, 329 mg, 0.69 mmol ), iron (233 mg, 4.17 mmol) and NM-Cl (26.0 mg, 0.49 mmol) in ethanol (12 ml) and water (4 ml) were refluxed for 3 hours. The mixture was left cool to room temperature and then filtered. The filtrate was concentrated in vacuo. Purification by ion exchange chromatography using an SCX column eluting with 0.7 M methanol ammonia and concentrating the appropriate fractions in vacuo gave a brown gum. As a result of additional purification by FCC with elution

- 64 046985

0-5% 7n. methanolic ammonia in CH2C12 gave the title compound (287 mg, 93%) as a light brown gum.

¹ H NMR (CDCl ₃ ): 2.37 (3H, br s), 2.59 (4H, s), 2.92-2.99 (4H, m), 3.79-3.86 (5H, m), 3.87 (3H, s), 6.71 ( 1H, s), 7.01 (1H, d), 7.27-7.34 (2H, m), 7.35-7.40 (1H, m), 7.57 (1H, s), 7.78 (1H, s), 8.17 (1H, s) , 8.32 (1H, d), 8.47-8.53 (1H, m); m/z: ES ⁺ MH ⁺ 444.54.

Intermediate 111. N[2-Methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-4-(1methylindol-3-yl)pyrimidin-2-amine.

1-Methylpiperazine (89 mg, 0.89 mmol), N(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3yl)pyrimidin-2-amine (Intermediate 129 (which may be prepared by the method described for intermediate 87), 350 mg, 0.89 mmol) and DIPEA (0.186 ml, 1.07 mmol) were suspended in DMA (6 ml) and sealed in a microwaving tube. The reaction mixture was heated under microwave conditions to 140°C for 1 hour and then cooled to room temperature. CH ₃ OH was added and an orange solid precipitated from solution. The solid was collected by filtration and washed with CH3OH and then with diethyl ether. The solid was then dried to give the title compound (339 mg, 80%) as an orange solid.

1H NMR: 2.26 (3H, s), 3.06-3.11 (4H, m), 3.88 (3H, s), 3.99 (3H, s), 6.86 (1H, s), 7.13 (1H, t), 7.23-7.29 (2H, m), 7.53 (1H, d), 8.10 (1H, s), 8.32-8.38 (3H, m), 8.81 (1H, s); (signals of 4 protons are not detected and are probably hidden under the DMSO peak); m/z: ES ⁺ MH ⁺ 474.56.

Intermediate 112. N[5-Chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-4-(3dimethylaminoazetidin-1-yl)-6-methoxybenzene-1,3-diamine.

Mixture of 5-chloro-N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1-methylindol-3yl)pyrimidin-2-amine (Intermediate 113, 285 mg , 0.56 mmol), iron (188 mg, 3.37 mmol) and NH ₄ Cl (22.51 mg, 0.42 mmol) in ethanol (9 ml) and water (3 ml) were refluxed for 2 hours. The mixture was then cooled and filtered through diatomaceous earth (Celite™). The filtrate was concentrated in vacuo and the resulting residue was dissolved in CH ₂ Cl ₂ . This solution was washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. As a result of purification by FCC eluting with 1-20% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (263 mg, 98%) as a brown dry film.

1H NMR (CDCl ₃ ): 2.21 (6H, s), 3.08-3.18 (1H, m), 3.30 (2H, br s), 3.58 (2H, t), 3.86 (3H, s), 3.88 (3H, s ), 3.93 (2H, t), 6.38 (1H, s), 7.2-7.42 (3H, m, partially hidden by the chloroform signal), 7.50 (1H, s), 7.99 (1H, s), 8.20 (1H, s) , 8.31 (1H, s), 8.63 (1H, d); m/z: ES+MH+ 478.

Intermediate 113. 5-Chloro-No[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine.

DIPEA (0.408 ml, 2.33 mmol) was added to the mixture of 5-chloro-N(4-fluoro-2-methoxy-5-nitrophenyl)4-(1-methylindol-3-yl)pyrimidin-2-amine-0 salt .8 toluene-4-sulfonic acid (Intermediate 87, 330 mg, 0.58 mmol) in DMA (3 ml). YNdimethylazetidine-3-amine dihydrochloride (Intermediate 26, 121 mg, 0.70 mmol) was then added in one portion. The mixture was heated under microwave conditions at 100°C for 0.5 h, then the mixture was cooled and diluted with CH3OH and absorbed on an SCX column. The column was washed with _CH3OH and eluted 1:1 with methanolic ammonia in _CH2Cl2 . The corresponding fractions were concentrated in vacuo. Further purification by FCC eluting with 1-10% CH ₃ OH in CH ₂ Cl ₂ gave the title compound (295 mg, 100%) as a brown gum.

1H NMR (CDCl ₃ ): 2.18 (6H, s), 3.13-3.24 (1H, m), 3.67-3.75 (2H, m), 3.89 (3H, s), 3.96 (3H, s), 4.13 (2H, t), 6.04 (1H, s), 7.21-7.29 (1H, m, partially hidden by the chloroform signal), 7.29-7.41 (3H, m), 8.22 (1H, s), 8.37 (1H, s), 8.46 (1H , d), 9.05 (1H, s); m/z: ES ⁺ MH ⁺ 508.

Intermediate 114: 4-(3-Dimethylaminoazetidin-1-yl)-6-methoxy-N[5-methyl-4-(1methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine.

Mixture of N[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-5-methyl-4-(1-methylindol-3yl)pyrimidin-2-amine (Intermediate 115, 210 mg, 0.43 mmol), iron (144 mg, 2.58 mmol) and NH4Cl (16.13 mg, 0.30 mmol) in ethanol (6 ml) and water (2 ml) were refluxed for 2 hours. The crude mixture was purified by ion exchange chromatography using an SCX column and eluting with 7 M methanolic ammonia. The appropriate fractions were combined and concentrated in vacuo on silica. As a result of additional purification via FCC eluting with 0-5% 7N. methanolic ammonia in CH ₂ Cl ₂ and after concentrating the corresponding fractions in vacuo, a brown foam was obtained. Further purification by ion exchange chromatography using an SCX column and eluting with 7 M methanol ammonia provided material which was concentrated in vacuo on silica. Further purification by FCC eluting with 0-4% CH3OH in CH2Cl2 gave the title compound (135 mg, 69%) as a brown foam.

1H NMR: 2.11 (6H, s), 2.35 (3H, s), 3.04 (1H, p), 3.44 (2H, t), 3.89 (3H, s), 3.92 (2H, s), 3.9-3.97 (2H , m),

- 65 046985

6.28 (1H, s), 7.12 (1H, dd), 7.2-7.26 (1H, m), 7.28 (1H, s), 7.48 (1H, d), 7.55 (1H, s), 8.00 (1H, s) , 8.15 (1H, s), 8.43 (1H, d); m/z: ES+MH+ 458.31.

Intermediate 115. >[4-(3-Dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-5methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine.

H,H-Dimethylazetidine-3-amine (Intermediate 26, 113 mg, 0.65 mmol) was added to the suspension of >(4-fluoro-2-methoxy-5-nitrophenyl)-5-methyl-4-(1-methylindole -3-yl)pyrimidin-2-amine (Intermediate 79, 250 mg, 0.61 mmol) and DIPEA (0.374 ml, 2.15 mmol) in 2,2,2-trifluoroethanol (5 ml). The mixture was heated under microwave conditions at 140°C for 1 hour. The cooled mixture was purified by ion exchange chromatography using an SCX column and eluting with 7 M methanol ammonia. The appropriate fractions were combined and concentrated in vacuo on silica. As a result of additional purification by FCC eluting with 0-4% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (213 mg, 71%) as an orange foam.

1H NMR: 2.13 (6H, s), 2.37 (3H, s), 3.09-3.16 (1H, m), 3.72 (2H, dd), 3.89 (3H, s), 3.93 (3H, s), 4-4.08 (2H, m), 6.27 (1H, s), 7.04 (1H, t), 7.20-7.26 (1H, m), 7.49 (1H, d), 7.90 (1H, s), 8.03 (1H, s), 8.23 (1H, s), 8.35 (1H, d), 8.46 (1H, s); m/z: ES ⁺ MH ⁺ 488.63.

Intermediate 116: 4-(3-Dimethylaminoazetidin-1-yl)-6-methoxy->[4-(1-methylindol3-yl)pyrimidin-2-yl]benzene-1,3-diamine.

Mixture of >[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1-methylindol-3yl)pyrimidin-2-amine (Intermediate 117, 160 mg, 0.34 mmol ), iron (113 mg, 2.03 mmol) and NH ₄ Cl (13.56 mg, 0.25 mmol) in ethanol (5 ml) and water (1.67 ml) were refluxed for 2 hours. The cooled mixture was purified by ion exchange chromatography using an SCX column and eluting with 1:1 7 M methanol ammonia in CH ₂ Cl ₂ . The appropriate fractions were combined and concentrated in vacuo. As a result of additional purification via FCC eluting with 0-5% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (120 mg, 80%) as a brown gum; m/z: ES ⁺ MH ⁺ 444.61.

Intermediate 117. >[4-(3-Dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4(1-methylindol-3-yl)pyrimidin-2-amine.

>>Dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 79 mg, 0.46 mmol) was added to the suspension of >>(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl) pyrimidin-2-amine (Intermediate 129 (which can be prepared as described for Intermediate 87), 150 mg, 0.38 mmol) and DIPEA (0.264 ml, 1.53 mmol) in 2,2,2-trifluoroethanol (3 ml). The mixture was heated under microwave conditions at 140°C for 1 hour. The mixture was then purified directly by ion exchange chromatography using an SCX column (50 g) and eluting with 1:1 7 M methanol ammonia in CH2Cl2. Concentration of the appropriate fractions in vacuo gave a red-brown solid. This solid was suspended in _CH3OH and the solid was collected by filtration, washed with CH3OH (10 mL) and dried in vacuo to give the title compound (160 mg, 89%) as a red solid; m/z: ES ⁺ MH ⁺ 474.61.

Intermediate 118. N-[5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-(3-dimethylaminoazetidin-1-yl)-6-methoxybenzene-1,3-diamine .

5-Chloro-N-[4-(3-dimethylαminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1H-indol-3yl)pyrimidin-2-amine mixture (Intermediate 119, 347 mg , 0.70 mmol), iron (235 mg, 4.22 mmol) and NH4Cl (26.3 mg, 0.49 mmol) in ethanol (9 ml) and water (3 ml) were refluxed for 1 hour The mixture was then purified by ion exchange chromatography using an SCX column and eluting with 7 M methanolic ammonia. The appropriate fractions were combined and concentrated in vacuo on silica. Further purification by FCC eluting with 0-5% 7M methanol ammonia in CH2Cl2 gave the title compound (323 mg, 99%) as a tan solid.

1H NMR: 2.12 (6H, s), 3.06 (1H, p), 3.48 (2H, t), 3.68 (3H, s), 3.92-4.02 (4H, m), 6.28 (1H, s), 6.91 (1H , s), 7.04 (1H, dd), 7.12-7.19 (1H, m), 7.44 (1H, d), 8.14 (1H, s), 8.28 (1H, s), 8.30 (1H, d), 8.46 ( 1H, s), 11.77 (1H, s); m/z: ES+MH+ 464.21.

Intermediate 119. 5-Chloro->[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1H-indol-3-yl)pyrimidin-2-amine.

>>Dimethylazetidine-3-amine (Intermediate 26, 144 mg, 0.83 mmol) was added to a suspension of 5-chloro->(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indole-3 -yl)pyrimidin-2-amine (Intermediate 76, 312 mg, 0.75 mmol) and DIPEA (0.460 ml, 2.64 mmol) in 2,2,2-trifluoroethanol (5 ml). The mixture was heated under microwave conditions at 140°C for 1 hour. The cooled mixture was purified by ion exchange chromatography using an SCX column and eluting with 7 M methanol ammonia. The appropriate fractions were combined and concentrated in vacuo on silica. As a result of additional purification by FCC eluting with 0-4% 7N. methanolic ammonia in CH ₂ Cl ₂ and trituration with diethyl ether gave the title compound (347 mg, 93%) as an orange solid.

- 66 046985 ¹ H NMR: 2.14 (6H, s), 3.09-3.18 (1H, m), 3.76 (2H, dd), 3.89 (3H, s), 4.01-4.11 (2H, m), 6.28 (1H, s), 6.98 (1H, t), 7.13-7.20 (1H, m), 7.46 (1H, d), 8.15 (1H, s), 8.23 (1H, d), 8.37 (1H, s), 8.47 (1H , s), 8.49 (1H, s), 11.84 (1H, s); m/z: ES+MH+ 494.16.

Intermediate 120. 2-({5-Amino-4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2methoxyphenyl}amino)-4-pyrazolo[1,5-a]pyrvdin-3-ylpyrimvdin-5 -carbonitrile.

Mixture of N-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxybenzene-1 ,3-diamine (Intermediate 18, 250 mg, 0.52 mmol), zinc cyanide (36.8 mg, 0.31 mmol), zinc powder (3.41 mg, 0.05 mmol) and 2-(dicyclohexylphosphino )2',4',6'-triisopropyl-1,1'-biphenyl (XPhos, 49.8 mg, 0.10 mmol) was stirred in DMA (2 ml) and purged with N2 for 0.25 h. Then added tris-(dibenzylidene-acetone)dipalladium(0) (47.8 mg, 0.05 mmol) and the mixture was heated at 95°C for 2 hours. The cooled mixture was then absorbed onto an SCX column, washed with CH ₃ OH and eluted with 7 M methanol ammonia solution. The appropriate fractions were combined and concentrated in vacuo. The resulting residue was suspended in CH3OH, then the mixture was filtered. The collected solid was filter dried to obtain the title compound (160 mg, 65%) as a tan powder.

1H NMR: (100°C) 1.78-1.92 (1H, m), 2.00-2.15 (1H, m), 2.26 (6H, s), 2.95-3.02 (1H, m), 3.02-3.07 (1H, m) , 3.07-3.13 (1H, m), 3.16-3.27 (2H, m), 3.68 (3H, s), 6.74 (1H, s), 6.95 (1H, s), 7.13 (1H, td), 7.33-7.43 (1H, m), 8.37 (1H, d), 8.64 (1H, s), 8.77 (1H, dt), 8.84 (1H, s), 8.91 (1H, s); m/z: ES ⁺ MH ⁺ 470.60.

Intermediate 121. 2-{[5-Amino-4-(2-dimethylaminoethylmethylamino)-2methoxyphenyl]amino}-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-5-carbonitrile.

N ⁴ -(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-N-(2-dimethylaminoethyl)-5-methoxyN-methylbenzene-1,2,4- triamine (Intermediate 33, 120 mg, 0.26 mmol), dicyanozinc (18.11 mg, 0.15 mmol), dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (24.50 mg, 0.05 mmol), tris-(dibenzylideneacetone)dipalladium(0) (23.5 mg, 0.03 mmol) and zinc powder (1.681 mg, 0.03 mmol) were suspended in degassed DMA (1.1 ml) and sealed in a microwave-safe tube. The mixture was then heated under microwave conditions to 95°C for 1 hour. The cooled mixture was then diluted with EtOAc (50 ml) and washed with sat. NaHCO ₃ (20 ml), water (20 ml) and sat. brine (10 ml). The organic solution was then concentrated in vacuo. Purification by FCC eluting with 0-20% CH3OH in CH ₂ Cl ₂ gave the title compound (36 mg, 31%) as a yellow gum.

1H NMR ( _CDCl3 ): 2.41 (6H, s), 2.60 (2H, s), 2.72 (3H, s), 3.07 (2H, t), 3.86 (3H, s), 6.72 (1H, s), 7.02 (1H, t), 7.41-7.53 (1H, m), 7.80 (2H, d), 8.60 (2H, d), 8.70 (1H, d), 9.09 (1H, s); m/z: ES ⁺ MH ⁺ 458.30.

Intermediate 122: 2-{[5-Amino-4-(3-dimethylaminoazetidin-1-yl)-2-methoxyphenyl]amino}-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-5-carbo nitrile.

>(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-(3-dimethylaminoazetidin-1-yl)-6methoxybenzene-1,3-diamine (Intermediate 24 , 297 mg, 0.64 mmol), tris-(dibenzylideneacetone)dipalladium(0) (14.62 mg, 0.02 mmol), 2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1, 1'biphenyl ('XPhos', 30.5 mg, 0.06 mmol) and dicyanozinc (45.0 mg, 0.38 mmol) were placed in a microwave tube under N ₂ . Poly(methylhydrosiloxane) (12 mg, 0.06 mmol) in degassed DMA (1.92 ml) was then added. The resulting mixture was then heated under microwave conditions at 120°C for 2 hours. The crude mixture was loaded onto an SCX column. The column was washed with water and then with CH ₃ OH/CH ₂ Cl ₂ . The target product was eluted from the column using 7 M methanolic ammonia in CH ₂ Cl ₂ and the pure fractions were combined and concentrated in vacuo. The residue was dissolved in CH ₃ OH/CH ₂ Cl ₂ and allowed to flow through a PL-Thiol MP SPE stratospheres SPE cartridge (available from Polymer Laboratories) by gravity. The resulting solution was concentrated in vacuo. Purification by FCC eluting with 0-5% CH3OH in CH2Cl2 and trituration with diethyl ether gave the title compound (139 mg, 48%) as a brown solid.

1H NMR (100°C): 2.18 (6H, s), 3.17 (1H, t), 3.60 (2H, t), 3.69 (3H, s), 3.87 (2H, br s), 4.00 (2H, t) , 6.32 (1H, s), 6.86 (1H, s), 7.11 (1H, t), 7.34-7.46 (1H, m), 8.34 (1H, d), 8.61 (1H, s), 8.72 (1H, br s), 8.76 (1H, d), 8.90 (1H, s); m/z: ES ⁺ MH ⁺ 456.23.

Intermediate 123. 4-[(3aR,6aR)-5-Methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4b]pyrrol-1 -yl]-6-methoxy-N-[4 -(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine.

Mixture of N-[4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-2-methoxy-5nitrophenyl] -4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 124, 256 mg, 0.51 mmol), iron powder (172 mg, 3.07 mmol) and NH4Cl (19.19 mg, 0.36 mmol) in ethanol (3 ml) and water (1 ml) was refluxed for 18 hours. The crude mixture was then purified by ion exchange chromatography using an SCX column. The target product was eluted from the column using 7 M methanolic ammonia and concentrated in vacuo. As a result of additional purification via FCC eluting with 0-5% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (198 mg, 82%) as a yellow foam.

1H NMR (CDCl ₃ ): 1.78 (1H, td), 2.07-2.13 (1H, m), 2.15 (1H, dd), 2.29 (3H, s), 2.47 (1H, dd), 2.57-2.65

- 67 046985 (2H, m), 2.82-2.95 (2H, m), 3.45 (1H, dt), 3.85 (3H, s), 3.88 (3H, s), 4.07 (1H, ddd), 6.74 (1H, s), 7.01 (1H, d), 7.27-7.35 (2H, m), 7.38 (1H, dd), 7.55 (1H, s), 7.79 (1H, s), 8.14 (1H, s), 8.33 (1H , d), 8.45-8.52 (1H, m); m/z: ES+MH+ 470.29.

Intermediate 124 N-[4-[(3αR,6αR)-5-Methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4b]pyrrol-1 -yl]-2-methoxy-5 -nitrophenyl]-4 -(1-methylindol-3-yl)pyrimidin-2-amine.

DIPEA (0.411 ml, 2.36 mmol) was added to a suspension of N(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1methylindol-3-yl)pyrimidin-2-amine (Intermediate 129, 425 mg, 0.94 mmol) and (3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-b]pyrrole (Intermediate 37, 250 mg, 1 .98 mmol) in 2,2,2-trifluoroethanol (4 ml). The mixture was heated under microwave conditions at 140°C for 1 hour. The cooled mixture was then purified by ion exchange chromatography using an SCX column. The target product was eluted from the column using 7 M methanolic ammonia and concentrated in vacuo. As a result of additional purification via FCC eluting with 0-5% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the impure title compound (396 mg, 84%) as an orange/red solid. This solid was dissolved in a minimal amount of CH ₂ Cl ₂ and the resulting solution was triturated with methanol. The resulting solid was collected by filtration to give the title compound (272 mg, 58%) as a red solid, which was used without further purification.

^1H NMR: 1.86 (1H, dd), 1.94-2.06 (1H, m), 2.12 (3H, s), 2.23 (1H, dd), 2.36-2.45 (2H, m), 2.52-2.58 (1H, m ) partially hidden by the DMSO peak, 2.91-3.04 (1H, m), 3.18 (1H, t), 3.49 (1H, td), 3.87 (3H, s), 3.95 (3H, s), 4.40 (1H, t), 6.61 (1H, s), 7.11 (1H, t), 7.18 (1H, d), 7.24 (1H, t), 7.51 (1H, d), 8.02 (1H, s), 8.27-8.31 (2H, m) , 8.34 (1H, d), 8.51 (1H, s); m/z: ES+MH+ 500.17.

Intermediate 125. ^-(2-Dimethylaminoethyl)-5-methoxy-H1-methyl-H ⁴ -[4-(4,5,6,7tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2 -yl]benzene-1,2,4-triamine.

A mixture of N-(2-dimethylaminoethyl)-2-methoxy-H'-methyl-5-nitro-H-[4-(4,5,6,7-tetrahydropyrazolo[1,5a]pyridin-3-yl)pyrimidin- 2-yl]benzene-1,4-diamine (Intermediate 126, 3.7 g,

7.93 mmol), iron (2.66 g, 47.58 mmol) and NH ₄ Cl (0.318 g, 5.95 mmol) in ethanol (120 ml) and water (40 ml) were refluxed for 2 .5 hours. The mixture was then cooled, filtered and concentrated. The solid was triturated in 5% CH ₃ OH/CH ₂ Cl ₂ (100 ml) for 15 minutes and then filtered. The filtrate was combined with the concentrated, filtered reaction mixture, washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. As a result of purification by FCC eluting with 0-2.5% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (2.50 g, 72%) as a brown gum.

1H NMR (CDCl ₃ ): 1.90-1.99 (2H, m), 2.04-2.13 (2H, m), 2.25 (6H, s), 2.37-2.42 (2H, m), 2.67 (3H, s), 2.92- 2.98 (2H, m), 3.25 (2H, t), 3.83 (3H, s), 4.00 (2H, s), 4.21 (2H, t), 6.70 (1H, s), 6.79 (1H, d), 7.48 (1H, s), 7.97 (2H, d), 8.30 (1H, d); m/z: ES+MH+ 437.39.

Intermediate 126. N-(2-Dimethylaminoethyl)-2-methoxy-N-methyl-5-nitro-N[4(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl) pyrimidin-2-yl]benzene-1,4-diamine.

Mixture of N(4-fluoro-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3yl)pyrimidin-2-amine (Intermediate 127, 3 0 g, 7.81 mmol), ^^,^-trimethylethane-1,2diamine (1.190 ml, 9.37 mmol) and DIPEA (1.620 ml, 9.37 mmol) in DMA (45 ml) heated at 100° C for 1.5 hours. The mixture was then cooled and absorbed onto an SCX column, washed with MeOH and eluted with methanolic ammonia. Fractions that contained the desired product were concentrated in vacuo and the resulting residue was dissolved in EtOAc. This solution was washed twice with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound (3.70 g, 102%) as an orange oil.

1H NMR (CDCl ₃ ): 1.90-1.98 (2H, m), 2.04-2.12 (2H, m), 2.26 (6H, s), 2.51-2.60 (2H, m), 2.87 (3H, s), 3.21- 3.30 (4H, m), 3.96 (3H, s), 4.20 (2H, t), 6.67 (1H, s), 6.88 (1H, d), 7.43 (1H, s), 7.95 (1H, s), 8.31 (1H, d), 9.00 (1H, s); m/z: ES+MH+ 467.63.

Intermediate 127. N(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine.

Mixture of 3-(2-chloropyrimidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (Intermediate 128, 3.6857 g, 15.70 mmol), 4-fluoro- 2-methoxy-5-nitroaniline (Intermediate 23, 2.92 g, 15.70 mmol) and p-toluenesulfonic acid hydrate (3.29 g, 17.28 mmol) in 2-pentanol (100 ml) were stirred at 85 °C in an N2 atmosphere for 1.5 hours. The mixture was then concentrated in vacuo and the resulting residue was dissolved in CH ₂ Cl ₂ (250 ml). This solution was washed with sat. NaHCO ₃ (2x100 ml), water (100 ml) and sat. brine (100 ml). The organic solution was concentrated in vacuo to obtain the crude product. Purification by FCC eluting with 0-10% CH3OH in CH2Cl2 gave an orange solid. This material was triturated with CH3OH to give a solid, which was collected by filtration and dried in vacuo to give the title compound (2.26 g, 37%) as a yellow solid.

1H NMR: 1.75-1.86 (2H, m), 1.92-2.04 (2H, m), 3.09 (2H, t), 4.02 (3H, s), 4.12 (2H, t), 7.13 (1H, d), 7.35 (1H, d), 8.14 (1H, s), 8.25 (1H, s), 8.42 (1H, d), 9.02 (1H, d); m/z: ES ⁺ MH ⁺ 385.

- 68 046985

Intermediate 128: 3-(2-Chloropyrimidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5a]pyridine.

bis-(Di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(P) (1.284 g, 1.81 mmol) was added in one portion to 3-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5a]pyridine (9 g, 36.27 mmol), 2,4-dichloropyrimidine (5.40 g, 36.27 mmol) and A 2 M solution of Na ₂ CO ₃ (39.9 ml, 79.80 mmol) in dimethoxyethane (250 ml) under N2 atmosphere. The resulting mixture was stirred at 85°C for 4 hours and then left to cool to room temperature. The mixture was then concentrated in vacuo and the residue was dissolved in CH ₂ Cl ₂ (500 ml). This solution was washed with water (200 ml) and then saturated. brine (200 ml). The organic solution was concentrated in vacuo. Purification by FCC eluting with 0-10% CH3OH in CH ₂ Cl ₂ gave the title compound (7.91 g, 93%) as an orange oil that solidified on standing.

1H NMR: 1.86 (2H, dt), 1.93-2.00 (2H, m), 3.11 (2H, t), 4.13 (2H, t), 7.68 (1H, d), 8.18 (1H, s), 8.57 (1H , d); m/z: ES+MH+ 235.

Intermediate 129. ^(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3yl)pyrimidin-2-amine

p-Toluenesulfonic acid hydrate (22.73 g, 119.5 mmol) was added in one portion to a mixture of 3-(2-chloropyrimidin-4-yl)-1-methylindole (Intermediate 130, 24.27 g, 99.58 mmol ) and 4-fluoro-2-methoxy-5-nitroaniline (Intermediate 23, 18.54 g, 99.58 mmol) in 2-pentanol (500 ml). The resulting mixture was stirred at 105°C for 2.5 hours and then cooled to room temperature. The resulting precipitate was collected by filtration, washed with 2-pentanol (50 ml) and dried under vacuum to obtain some of the desired product as a yellow solid. The filtrate was cooled and the resulting precipitate was collected by filtration and washed with 2-pentanol (10 ml). Two batches of product were combined and triturated with CH3CN to give a solid, which was collected by filtration and dried under vacuum to give the title compound (37.4 g, 95%) as a yellow solid.

1H NMR: 3.92 (3H, s), 4.01 (3H, s), 7.13 (1H, dd), 7.27-7.36 (1H, m), 7.40-7.51 (2H, m), 7.59 (1H, d), 8.26 (1H, t), 8.35 (1H, d), 8.61 (1H, s), 8.85 (1H, d), 9.46 (1H, s); m/z: ES-M ^- 392.

Intermediate 130: 3-(2-Chloropyrimidin-4-yl)-1-methylindole.

NaH (1.707 g, 42.68 mmol, 40% dispersion in mineral oil) was added in small portions to the cooled (0° C.) mixture of 3-(2-chloropyrimidin-4-yl)-N-indole (Intermediate 131, 8.168 g, 35.57 mmol) in THF (250 ml). The resulting mixture was stirred at 0°C for 0.5 h and then CH ₃ I (2.67 ml, 42.68 mmol) was added and the mixture was stirred at 0°C for an additional 3 hours. The reaction mixture was quenched by adding sat. NaHCO ₃ (25 ml). The mixture was then diluted with EtOAc (100 ml) and the resulting solution was washed with sat. NaHCO ₃ (50 ml), water (50 ml) and sat. brine (50 ml). The organic solution was then concentrated in vacuo. Purification by FCC eluting with 0-20% CH3OH in CH2Cl2 provided the title compound (8.35 g, 96%) as a pale yellow solid.

1H NMR: 3.90 (3H, s), 7.30 (2H, pd), 7.54-7.60 (1H, m), 7.82 (1H, d), 8.38-8.44 (1H, m), 8.49 (1H, s), 8.53 (1H, d); m/z: ES+ MH ⁺ 244.

Intermediate 130: 3-(2-Chloropyrimidin-4-yl)-1-methylindole (alternate synthesis).

AlCl ₃ (197 g, 1.477 mol) was added portionwise to a solution of 2,4-dichloro-pyrimidine (200 g, 1342 mmol) in dimethoxyethane (2 L), maintaining the temperature below 30° C., and the mixture was stirred for 10 minutes. 1-Methylindole (0.172 L, 1.342 mol) was then added and the mixture was heated to 80°C for 2 hours and then allowed to cool overnight. The mixture was then poured into stirred water (20 L) and then stirred for 1 additional hour. The mixture was then filtered and the resulting solid was washed with water (3 L). The solid was then air dried for 16 hours to give a pink solid (315 g). This solid was then stirred in CH ₃ CN (6.3 L, reflux) for 1.5 hours, after which water (630 ml) was added. The mixture was then left to cool to room temperature. and stirred for 18 hours. The mixture was then stirred at 5°C for 0.5 hours, then the resulting solid was collected by filtration. The solid was then washed with cold 10% CH ₃ CN/water (2 x 1 L) and then dried to give the title compound (220 g, 67%) as a cream solid.

- 69 046985

Intermediate 131: 3-(2-Chloropyrimidin-4-yl)-1H-indole.

CH ₃ MgBr (3 M in diethyl ether, 22.68 ml, 68.03 mmol) was added dropwise over a period of 10 min to a stirred solution of N-indole (7.97 g, 68.03 mmol) in 1.2 -dichloroethane (250 ml) at 0°C in an N2 atmosphere. The resulting solution was stirred for 15 minutes and then 2,4-dichloropyrimidine (15.00 g, 100.69 mmol) was added in one portion. The resulting solution was left to warm to room temperature. and stirred for 16 additional hours. The reaction mixture was quenched by adding CH3OH (25 ml), then the mixture was concentrated in vacuo and absorbed onto silica. Purification by FCC eluting with 0-20% CH3OH in CH ₂ Cl ₂ gave the title compound (7.17 g, 46%) as a yellow solid.

1H NMR: 7.20-7.28 (2H, m), 7.49-7.53 (1H, m), 7.91 (1H, d), 8.42 (1H, dd), 8.50 (1H, d), 8.53 (1H, d), 12.06 (1H, s); m/z: ES+MH+ 230.

Intermediate 132. 4-[(3aR,6aR)-5-Methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-6-methoxy-Io[ 4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]benzene1,3-diamine.

Mixture of N-{4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-2-methoxy-5nitrophenyl} -4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 133, 400 mg, 0.82 mmol), iron (273 mg, 4.89 mmol) and NH ₄ Cl (30.5 mg, 0.57 mmol) in ethanol (12 ml) and water (4 ml) were refluxed for 4 hours and then stirred at room temperature. during the night. Partial purification by ion exchange chromatography using an SCX column and eluting with 7 M methanol ammonia provided the crude material, which was concentrated in vacuo on silica. As a result of purification by FCC eluting with 0-5% 7N. methanol ammonia in CH ₂ Cl ₂ obtained a contaminated product in the form of a brown resin. As a result of additional purification via FCC, eluting with 0-2% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (123 mg, 33%) as a brown gum; m/z: ES ⁺ MH ⁺ 461.26.

Intermediate 133. N-{4-[(3aR,6aR)-5-Methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-2-methoxy -5-nitrophenyl}-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2amine.

DIPEA (0.583 ml, 3.35 mmol) was added to the suspension of Ju(4-fluoro-2-methoxy-5-nitrophenyl)-4(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3- yl)pyrimidin-2-amine (Intermediate 127, 515 mg, 1.34 mmol) and (3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3 ,4-b]pyrrole (Intermediate 37, 186 mg, 1.47 mmol) in 2,2,2-trifluoroethanol (5 ml) and the mixture was heated under microwave conditions at 140°C for 1 hour. After cooling, the mixture partially purified by ion exchange chromatography using an SCX column eluting with 7 M methanol ammonia and then concentrated in vacuo on silica. As a result of purification by FCC eluting with 0-5% 7N. methanolic ammonia in CH2Cl2 gave the title compound (400 mg, 61%) as an orange/red foam.

1H NMR (CDCl ₃ ): 1.87 (1H, dd), 1.90-1.98 (2H, m), 2.03-2.14 (3H, m), 2.20 (3H, s), 2.28 (1H, dd), 2.45 (2H, ddd), 2.60-2.67 (1H, m), 2.97-3.07 (1H, m), 3.18-3.34 (3H, m), 3.48-3.58 (1H, m), 3.96 (3H, s), 4.20 (2H, t), 4.40 (1H, ddd), 6.43 (1H, s), 6.86 (1H, d), 7.35 (1H, s), 7.95 (1H, s), 8.30 (1H, d), 8.92 (1H, s ); m/z: ES ⁺ MH ⁺ 491.15.

Intermediate 134. 4-[(3K)-3-Dimethylaminopyrrolidin-1-yl]-6-methoxy-Io[4(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl) pyrimidin-2-yl]benzene-1,3-diamine.

Mixture N{4-[(3K)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3 -yl)pyrimidin-2-amine (Intermediate 135, 198.7 mg, 0.42 mmol), iron (139 mg, 2.49 mmol) and NH4Cl (15.6 mg, 0.29 mmol) in ethanol ( 15 ml) and water (5 ml) were refluxed for 2.5 hours. The mixture was then left to cool to room temperature, filtered and concentrated in vacuo. Partial purification by ion exchange chromatography using an SCX column and eluting with 0.7 M methanol ammonia provided the crude material as a yellow gum. As a result of additional purification via FCC eluting with 0-5% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (159 mg, 85%) as a brown foam.

1H NMR (CDCl ₃ ): 1.83-1.97 (3H, m), 2.05-2.17 (3H, m), 2.29 (6H, s), 2.83-2.91 (1H, m), 2.98-3.08 (2H, m), 3.15-3.20 (2H, m), 3.24 (2H, t), 3.69 (2H, s), 3.83 (3H, s), 4.20 (2H, t), 6.69 (1H, s), 6.78 (1H, d) , 7.45 (1H, s), 7.97 (2H, d), 8.29 (1H, d); m/z: ES+MH+ 449.65.

Intermediate 135 3-yl)pyrimidin-2-amine.

(3C)-SiOdimethylpyrrolidin-3-amine (64 mg, 0.56 mmol), Sio(4-fluoro-2-methoxy-5-nitrophenyl)-4(4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 127, 267 mg, 0.53 mmol) and DIPEA (0.186 ml, 1.07 mmol) were suspended in DMA (2 ml), sealed in a tube for microwave treatment and then heated to 140°C for 1 hour in a microwave reactor. After cooling to room temperature. the mixture was partially purified by ion exchange chromatography,

- 70 046985 using SCX column. The column was first washed with CH3OH and then eluted with 0.7 M methanolic ammonia. The pure fractions were concentrated in vacuo to give the crude material as an orange gum. As a result of purification by FCC eluting with 0-5% 7N. methanolic ammonia in CH2Cl2 gave the title compound (201 mg, 79%) as an orange gum.

1H NMR (CDCl ₃ ): 1.89-1.98 (3H, m), 2.05-2.12 (2H, m), 2.16-2.23 (1H, m), 2.30 (6H, s), 2.78-2.87 (1H, m), 3.14-3.37 (5H, m), 3.54 (1H, td), 3.96 (3H, s), 4.20 (2H, t), 6.34 (1H, s), 6.85 (1H, d), 7.33 (1H, s) , 7.95 (1H, s), 8.30 (1H, d), 8.95 (1H, s); m/z: ES ⁺ MH ⁺ 479.60.

Intermediate 136. 4-Methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N'-[4(4,5,6,7-tetrahydropyrazolo[1,5- a] pyridin-3 -yl) pyrimidin-2 -yl] benzene-1,3-diamine.

1,1-Bis(di-tert-butylphosphino)ferrocene-palladium dichloride (16.7 mg, 0.03 mmol) was added to the solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (139 mg, 0.62 mmol), 4-bromo-6-methoxy-N-[4-(4,5,6,7 -tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2yl]benzene-1,3-diamine (Intermediate 137, 215 mg, 0.52 mmol) and K ₃ PO ₄ (220 mg, 1, 04 mmol) in 1,4-dioxane (6 ml) and water (1.5 ml, degassed for 20 min before use). The mixture was then heated at 100°C for 1 hour and then concentrated in vacuo. The resulting residue was dissolved in EtOAc and the solution was washed three times with water, then with brine. The solution was then dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 0-10% methanolic ammonia in CH ₂ Cl ₂ and trituration with diethyl ether gave the title compound (160 mg, 72%) as a tan solid.

¹ H NMR: 1.79-1.87 (2H, m), 1.96-2.03 (2H, m), 2.29 (3H, s), 2.34-2.40 (2H, m), 2.58 (2H, t), 2.98-3.02 (2H , m), 3.15 (2H, t), 3.75 (3H, s), 4.12 (2H, t), 4.32 (2H, br s), 5.67-5.71 (1H, m), 6.60 (1H, s), 7.01 (1H, d), 7.58 (1H, s), 7.69 (1H, s), 8.09 (1H, s), 8.32 (1H, d); m/z: ES ⁺ MH ⁺ 432.72.

Intermediate 137. 4-Bromo-6-methoxy-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1, 3-diamine

No.(4-Bromo-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin2-amine (Intermediate 138, 944 mg , 2.12 mmol), iron (710 mg, 12.7 mmol) and NH ₄ Cl (85 mg, 1.59 mmol) in ethanol (40 ml) and water (13 ml) were refluxed for 1. 5 hours. The mixture was then cooled and filtered. The residue was triturated with 10% CH ₃ OH in CH ₂ Cl ₂ (30 ml) for 15 minutes and then filtered. The residue was triturated again with 10% CH ₃ OH in CH ₂ Cl ₂ (30 ml) and filtered. The combined filtrates were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 0-5% CH ₃ OH in CH ₂ Cl ₂ and trituration with diethyl ether gave the title compound (814 mg, 92%) as a brown solid.

1H NMR: 1.80-1.87 (2H, m), 1.96-2.03 (2H, m), 3.13 (2H, t), 3.77 (3H, s), 4.12 (2H, t), 4.82 (2H, s), 7.02 (1H, s), 7.05 (1H, d), 7.75 (1H, s), 7.77 (1H, s), 8.10 (1H, s), 8.34 (1H, d); m/z: ES ⁺ MH ⁺ 415/417.

Intermediate 138. N(4-Bromo-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine.

A solution of 3-(2-chloropyrimidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (Intermediate 128, 0.893 g, 3.80 mmol), p-toluenesulfonic acid monohydrate ( 1.034 g, 5.43 mmol) and 4-bromo-2-methoxy-5-nitroaniline (Intermediate 4, 0.895 g, 3.62 mmol) in 2-pentanol (35 ml) were refluxed for 16 h at atmosphere N ₂ . The mixture was then left to cool and concentrated in vacuo. The resulting residue was triturated in CH ₃ CN until a yellow precipitate formed. The solid was collected by filtration and washed with diethyl ether. The solid was then dissolved in 10% CH3OH in CH ₂ Cl ₂ and the resulting solution was washed twice with sat. NaHCO3, then water. The solution was then dried (MgSO ₄ ) and concentrated in vacuo. The resulting residue was triturated with CH3CN and the resulting solid was collected by filtration, washed with diethyl ether and then air-dried to give the title compound (0.946 g, 59%) as a yellow solid.

1H NMR: 1.80-1.87 (2H, m), 1.96-2.03 (2H, m), 3.11 (2H, t), 4.04 (3H, s), 4.13 (2H, t), 7.17 (1H, d), 7.50 (1H, s), 8.13 (1H, s), 8.21 (1H, s), 8.45 (1H, d), 9.10 (1H, s); m/z: ES ⁺ MH ⁺ 445/447.

Intermediate 139: 4-(3-Dimethylaminoazetidin-1-yl)-6-methoxy-N[4-(4,5,6,7tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl ] benzene-1,3-diamine.

Mixture of N[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidine -2-amine (Intermediate 140, 130 mg, 0.28 mmol), iron (94 mg, 1.68 mmol) and NH4Cl (10.48 mg, 0.20 mmol) in ethanol (12 ml) and water ( 4 ml) was refluxed for 2.5 hours. The mixture was left to cool to room temperature, filtered and concentrated in vacuo. Partial purification by ion exchange chromatography using an SCX column and eluting with 0.7 M methanol ammonia provided the crude material as a brown gum. As a result of additional purification via FCC eluting with 0-5% 7N. methanolic ammonia in CH2Cl2 gave the title compound (111 mg, 91%) as a brown gum.

1H NMR (CDCl ₃ ): 1.90-1.98 (2H, m), 2.04-2.12 (2H, m), 2.20 (6H, s), 3.08-3.16 (1H, m), 3.23 (2H, t), 3.35

- 71 046985 (1H, s), 3.56 (2H, t), 3.84 (3H, s), 3.93 (2H, dd), 4.20 (2H, t), 6.37 (1H, s), 6.76 (1H, d) , 7.35 (1H, s), 7.87 (1H, s), 7.95 (1H, s), 8.28 (1H, d); m/z: ES ⁺ MH ⁺ 435.58.

Intermediate 140. N[4-(3-Dimethylaminoazetdin-1-yl)-2-methoxy-5-nitrophenyl]-4(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl )pyrimidine-2-amine.

K^dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 109 mg, 0.63 mmol), Na(4-fluoro-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[ 1,5-a]pyridin-3yl)pyrimidin-2-amine (Intermediate 127, 300 mg, 0.60 mmol), DIPEA (0.386 ml, 2.22 mmol) and DMA (4 ml) were sealed in a tube for microwave treatment and heated to 140°C for 1 hour in a microwave reactor. After cooling to room temperature. the mixture was partially purified by ion exchange chromatography using an SCX column. The column was first washed with CH ₃ OH, and then the target product was eluted from the column using 0.7 M methanolic ammonia. Pure fractions were concentrated in vacuo to give an orange gum. As a result of additional purification via FCC eluting with 0-5% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (140 mg, 50%) as an orange solid.

^1H NMR ( _CDCl3 ): 1.90-1.98 (2H, m), 2.05-2.12 (2H, m), 2.20 (6H, s), 3.15-3.23 (1H, m), 3.28 (2H, t), 3.69 (2H, dd), 3.96 (3H, s), 4.18 (4H, dt), 6.03 (1H, s), 6.87 (1H, d), 7.35 (1H, s), 7.97 (1H, s), 8.31 ( 1H, d), 9.02 (1H, s); m/z: ES ⁺ MH ⁺ 465.61.

Intermediate 141 ]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine.

N[2-Methoxy-4-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-5-nitrophenyl]-4-(4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 142, 320 mg, 0.65 mmol), iron (219 mg, 3.91 mmol) and NH ₄ Cl (26.2 mg, 0.49 mmol) was refluxed in ethanol (18 ml) and water (6 ml) for 4 hours. The mixture was then cooled, filtered and concentrated in vacuo. The resulting residue was triturated with 10% CH3OH in CH ₂ Cl ₂ (15 ml) for 15 minutes and then the mixture was filtered. The residue was triturated again with 10% CH3OH in CH ₂ Cl ₂ (15 ml) and then the mixture was filtered. The combined filtrates were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. As a result of purification by FCC eluting with 2% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (251 mg, 84%) as a brown gum that crystallized on standing.

1H NMR: 1.64-1.76 (2H, m), 1.75-1.87 (2H, m), 1.91-2.03 (2H, m), 2.08 (2H, dd), 2.39 (3H, s), 2.63 (2H, t) , 3.06 (2H, t), 3.56 (2H, d), 3.72 (3H, s), 3.82 (2H, d), 4.01 (2H, s), 4.10 (2H, t), 6.25 (1H, s), 6.91 (1H, d), 7.21 (1H, s), 7.67 (1H, s), 8.04 (1H, s), 8.23 (1H, d); m/z: ES+MH+ 461.37.

Intermediate 142. N[2-Methoxy-4-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-5nitrophenyl]-4-(4,5,6,7-tetrahydropyrazolo [1, 5-a]pyridin-3-yl)pyrimidin-2-amine.

No.(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin2-amine (Intermediate 127, 300 mg , 0.78 mmol), 8-methyl-2,8-diazaspiro[3.4]octane (Intermediate 47, 118 mg, 0.94 mmol) and DIPEA (0.162 ml, 0.94 mmol) were heated at 100 °C in DMA (4 ml) for 1.75 hours The mixture was then absorbed onto an SCX column, then the column was washed with CH ₃ OH and then eluted with 1:1 7 M methanolic ammonia in CH ₂ Cl ₂ . Fractions that contained the target product were combined and concentrated in vacuo. Purification by FCC eluting with 2.5% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (321 mg, 84%) as an orange foam.

1H NMR: 1.62-1.74 (2H, m), 1.74-1.85 (2H, m), 1.91-2.00 (2H, m), 2.00-2.06 (2H, m), 2.38 (3H, s), 2.65 (2H, t), 3.03 (2H, t), 3.71 (2H, d), 3.95 (3H, s), 4.04-4.15 (4H, m), 6.27 (1H, s), 7.01 (1H, d), 8.01 (1H , s), 8.09 (1H, s), 8.33 (1H, d), 8.54 (1H, s); m/z: ES+MH+ 491.6.

Intermediate 143. 4-Methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N'-[4-(1methylindol-3-yl)pyrimidin-2-yl]benzene - 1,3-diamine

1,1-Bis-(Di-tert-butylphosphino)ferrocene-palladium dichloride (16.74 mg, 0.03 mmol) was added to the solution containing 1-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (139 mg, 0.62 mmol), 4-bromo-6-methoxy-N[4-(1-methylindole-3 -yl)pyrimidin-2-yl]benzene-1,3diamine (Intermediate 144, 220 mg, 0.52 mmol) and _K3PO4 ( ₂₂₀ mg, 1.04 mmol) in 1,4-dioxane (6 ml ) and water (1.5 ml, degassed for 20 min before use). The mixture was heated at 100°C for 1 hour and then concentrated in vacuo. The resulting residue was dissolved in EtOAc. This solution was washed with water (3x), brine and then dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 0-10% methanolic ammonia in CH ₂ Cl ₂ and trituration with diethyl ether gave the title compound (191 mg, 84%) as a tan solid.

1H NMR: 2.31 (3H, s), 2.37-2.43 (2H, m), 2.61 (2H, t), 3.01-3.04 (2H, m), 3.76 (3H, s), 3.89 (3H, s), 4.37 (2H, br s), 5.70-5.73 (1H, m), 6.63 (1H, s), 7.18-7.22 (2H, m), 7.25-7.29 (1H, m), 7.54 (1H, d), 7.63 ( 1H, s), 7.81 (1H, s), 8.31 (1H, d), 8.34 (1H, s), 8.46 (1H, d); m/z: ES+MH+ 441.57.

Intermediate 144: 4-Bromo-6-methoxy-N[4-(1-methylindol-3-yl)pyrimidin-2yl]benzene-1,3-diamine.

No.(4-Bromo-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate with

- 72 046985 unit 145, 1.074 g, 2.36 mmol), iron (0.792 g, 14.19 mmol) and NH ₄ Cl (95 mg, 1.77 mmol) were refluxed in ethanol (39 ml) and water (13 ml) for 1.5 hours. The mixture was then cooled and concentrated in vacuo. The resulting residue was triturated with 10% CH3OH in CH ₂ Cl ₂ (30 ml) for 15 minutes and then the mixture was filtered. The residue was triturated again with 10% CH3OH in CH ₂ Cl ₂ (30 ml) and then the mixture was filtered. The combined filtrates were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with CH ₂ Cl ₂ gave the title compound (0.937 g, 93%) as a cream colored foam.

1H NMR: 3.79 (3H, s), 3.89 (3H, s), 4.86 (2H, s), 7.06 (1H, s), 7.18-7.30 (3H, m), 7.54 (1H, d), 7.83 (1H , s), 7.87 (1H, s), 8.33 (1H, d), 8.35 (1H, s), 8.43 (1H, d); m/z: ES ⁺ MH ⁺ 424/426.

Intermediate 145. No. (4-Bromo-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3yl)pyrimidin-2-amine

A solution of 3-(2-chloropyrimidin-4-yl)-1-methylindole (Intermediate 130, 0.829 g, 3.40 mmol), p-toluenesulfonic acid monohydrate (0.924 g, 4.86 mmol) and 4-bromo-2 -methoxy-5nitroaniline (Intermediate 4, 0.8 g, 3.24 mmol) was refluxed in 2-pentanol (32 ml) under N ₂ for 18 hours. The mixture was then allowed to cool and then concentrated in vacuo . The resulting residue was triturated with CH3CN until a yellow precipitate formed. This solid was collected by filtration and washed with diethyl ether. The solid was suspended in 10% CH3OH in CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ (2x) and then with water. The organic solution was then concentrated in vacuo and the resulting residue was triturated in CH ₃ CN/water. The mixture was then filtered and the collected solid was washed with CH ₃ CN followed by diethyl ether and then air dried to give the title compound (1.082 g, 74%) as a yellow solid.

1H NMR: 3.90 (3H, s), 4.05 (3H, s), 7.15-7.21 (1H, m), 7.26-7.31 (1H, m), 7.36 (1H, d), 7.52 (1H, s), 7.56 (1H, d), 8.34 (1H, s), 8.39 (1H, s), 8.40-8.45 (2H, m), 9.20 (1H, s); m/z: ES ⁺ MH ⁺ 454/456.

Intermediate 146. 4-Methoxy-6-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-N-[4-(1methylindol-3-yl)pyrimidin-2-yl]benzene- 1,3-diamine

Mixture of N[2-methoxy-4-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-5-nitrophenyl]-4-(1-methylindol-3yl)pyrimidin-2-amine (Intermediate compound 147, 200 mg, 0.40 mmol), iron (134 mg, 2.40 mmol) and NH ₄ Cl (16 mg, 0.30 mmol), ethanol (18 ml) and water (6 ml) were refluxed refrigerator for 1 hour, then the mixture was left to cool. The mixture was then filtered and concentrated in vacuo. The resulting residue was triturated with 10% CH3OH in CH2Cl2 (15 ml) for 15 min and then the mixture was filtered. The residue was triturated again with 10% CH3OH in CH2Cl2 (15 ml) and then the mixture was filtered. The combined filtrates were washed with brine, dried (Na2SO4) and concentrated in vacuo. As a result of purification by FCC eluting with 2% 7N. methanolic ammonia in CH ₂ Cl ₂ gave the title compound (144 mg, 77%) as a dark green foam.

1H NMR: 1.66-1.80 (2H, m), 2.06-2.16 (2H, m), 2.42 (3H, s), 2.66 (2H, t), 3.59 (2H, d), 3.75 (3H, s), 3.833 .91 (5H, m), 4.01 (2H, s), 6.30 (1H, s), 7.09 (1H, d), 7.16 (1H, t), 7.21-7.28 (1H, m), 7.31 (1H, s ), 7.51 (1H, d), 7.70 (1H, s), 8.23 (1H, d), 8.26 (1H, s), 8.43 (1H, d); m/z: ES ⁺ MH ⁺ 470.7.

Intermediate 147. N[2-Methoxy-4-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-5nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2- amine.

Mixture of N(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 129, 300 mg, 0.76 mmol), 8-methyl- 2,8-diazaspiro[3.4]octane (Intermediate 47, 115 mg, 0.92 mmol), DIPEA (0.158 ml, 0.92 mmol) and DMA (4 ml) were heated at 100°C for 1 hour. Then the mixture was absorbed onto an SCX column and the column was washed with CH3OH. The column was then eluted 1:1 with methanolic ammonia in CH ₂ Cl ₂ and fractions containing the desired product were combined and concentrated in vacuo. Purification by FCC eluting with 1.5% CH3OH in CH ₂ Cl ₂ gave the title compound (209 mg, 55%) as an orange solid.

1H NMR: 1.71 (2H, dt), 2.00-2.10 (2H, m), 2.40 (3H, s), 2.67 (2H, t), 3.74 (2H, d), 3.88 (3H, s), 3.96 (3H , s), 4.11 (2H, d), 6.31 (1H, s), 7.12 (1H, t), 7.20 (1H, d), 7.25 (1H, dd), 7.52 (1H, d), 8.02 (1H, s), 8.28-8.34 (2H, m), 8.36 (1H, d), 8.63 (1H, s); m/z: ES ⁺ MH ⁺ 500.6.

Intermediate 148. 4-[^)-3-Dimethylaminopyrrolidin-1-yl]-6-methoxy-N4-(1methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine.

A mixture of N-[4-[(3S)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl]-4-(1-methylindol-3

- 73 046985 yl)pyrimidin-2-amine (Intermediate 149, 230 mg, 0.47 mmol), iron (158 mg, 2.83 mmol), NH ₄ Cl (17.7 mg, 0.33 mmol), ethanol (9 ml) and water (3 ml) were refluxed for 50 min. It was determined that the reaction was not complete, so additional iron (158 mg, 2.83 mmol) and NH ₄ Cl (17.7 mg, 0.33 mmol) were added and the mixture was refluxed for an additional 0.5 hour . After cooling, the mixture was filtered and concentrated in vacuo. Purification by FCC eluting with 1.5-7% 7 M methanolic ammonia in CH ₂ Cl ₂ gave the title compound (187 mg, 87%) as a gray foam.

^1H NMR: 1.78 (1H, m), 2.06 (1H, m), 2.20 (6H, s), 2.86 (1H, d), 2.90-3.01 (2H, m), 3.12 (1H, m), 3.153. 23 (1H, m), 3.76 (3H, s), 3.88 (3H, s), 4.27 (2H, s), 6.72 (1H, s), 7.14 (1H, d), 7.15-7.21 (1H, m) , 7.22-7.34 (1H, m), 7.50 (1H, s), 7.52 (1H, d), 7.74 (1H, s), 8.26 (1H, s), 8.28 (1H, s), 8.43 (1H, d ); m/z: ES ⁺ MH ⁺ 458.75.

Intermediate 149. N-{4-[(3S)-3-Dimethylaminopyrrolidin-1-yl]-2-methoxy-5nitrophenyl}-4-(1-methylindol-3-yl)pyrimidin-2-amine.

N(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 129, 295 mg, 0.75 mmol), ((3S)- N,N-dimethylpyrrolidin-3-amine (103 mg, 0.90 mmol) and DIPEA (0.196 ml, 1.13 mmol) were dissolved in DMA (3 ml) and sealed in a microwaving tube. The mixture was heated to 100°. C for 45 min in a microwave reactor, then cooled to RT, diluted with CH ₃ OH and absorbed on an SCX column. The column was washed with CH3OH and then eluted with 1:1 methanolic ammonia in CH ₂ Cl ₂ . combined and concentrated in vacuo. Purification by FCC eluting with 2-7% methanolic ammonia in CH ₂ Cl ₂ gave the title compound (235 mg, 64%) as a red solid.

^1H NMR: 1.83 (1H, m), 2.17 (1H, m), 2.22 (6H, s), 2.72-2.86 (1H, m), 3.17 (2H, m), 3.26 (1H, m), 3.47 ( 1H, m), 3.88 (3H, s), 3.97 (3H, s), 6.58 (1H, s), 7.12 (1H, t), 7.19 (1H, d), 7.21-7.31 (1H, m), 7.52 (1H, d), 8.01 (1H, s), 8.23-8.33 (2H, m), 8.36 (1H, d), 8.58 (1H, s); m/z: ES ^- MH ⁺ 488.35.

Intermediate 150: 4-Methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N-(4pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl )benzene-1,3-diamine.

A mixture of N-[2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitrophenyl]-4-pyrazolo[1,5a]pyridin-3-ylpyrimidin-2 -amine (Intermediate 151, 285 mg, 0.56 mmol), iron (188 mg, 3.36 mmol), NH ₄ Cl (21 mg, 0.39 mmol), ethanol (10.5 ml) and water ( 3.5 ml) was refluxed for 1.5 hours. It was determined that the reaction was not complete, so additional amounts of NH ₄ Cl (21 mg, 0.39 mmol) and iron (188 mg, 3.36 mmol) were added ) and the mixture was refluxed for an additional 1.5 hours. After cooling, the mixture was filtered and concentrated in vacuo. As a result of purification by FCC eluting with 2-10% 7N. methanolic ammonia in CH2Cl2 gave the title compound (183 mg, 69%) as an orange gum, which was used without further purification.

1H NMR: 2.30 (3H, s), 2.36-2.45 (2H, m), 2.60 (2H, t), 2.98-3.06 (2H, m), 3.74 (3H, s), 4.34 (2H, s), 5.73 (1H, s), 6.64 (1H, s), 7.09 (1H, m), 7.26 (1H, d), 7.38-7.49 (2H, m), 8.00 (1H, s), 8.35 (1H, d), 8.58 (1H, d), 8.80 (2H, m); m/z: ES ⁺ MH ⁺ 427.

Intermediate 151. N-[2-Methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3- ilpyrimidin-2-amine.

A solution of 3-(2-chloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine (Intermediate 152, 256 mg, 1.00 mmol), p-toluenesulfonic acid monohydrate (271 mg, 1.43 mmol) and 2-methoxy-4-(1methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitroaniline (Intermediate 3, 250 mg, 0.95 mmol) and 2-pentanol (12 ml) were boiled with reflux for 4 hours under N2 atmosphere. The mixture was then concentrated in vacuo and the residue was dissolved in CH3OH. This solution was purified by ion exchange chromatography using an SCX column eluting with 7 M methanol ammonia. Fractions containing the desired product were concentrated in vacuo to obtain a residue which was dissolved in hot DMF (10 ml). This solution was filtered and concentrated in vacuo to obtain a gum, which was triturated with CH ₃ CN (10 ml) to obtain the title compound (285 mg, 66%) as a yellow powder.

1H NMR: 2.36 (5H, s), 2.67 (2H, s), 3.07 (2H, s), 4.02 (3H, s), 5.66 (1H, s), 7.00 (1H, s), 7.12 (1H, t ), 7.41 (1H, m), 7.45 (1H, m), 8.45 (2H, t), 8.59 (1H, d), 8.83 (2H, t), 8.90 (1H, s); m/z: ES-MH ^- 456.

Intermediate 152: 3-(2-Chloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine.

K ₂ CO ₃ (5.18 g, 37.50 mmol) was added to 1-aminopyridinium iodide (4.50 g, 20.25 mmol) and (E)-2-chloro-4-(2-ethoxyvinyl)pyrimidine ( Intermediate 153, 2.77 g, 15 mmol) in DMF (20 ml) at 25°C. The resulting dark blue suspension was stirred at 25°C for 15 hours (the color turned dark red) and then heated to 110°C for 2 hours. After cooling, the mixture was added to water (100 ml) and the resulting brown solid was collected by filtration, washed with water and dried by aspiration. The aqueous filtrate was extracted with EtOAc (2x100 ml) and the combined organic solutions were washed with water (4x100 ml) and saturated brine (50 ml). The solution was then dried (MgSO ₄ ) and concentrated in vacuo. The resulting residue was combined with the previously collected co

- 74 046985 richen solid and dissolved in THF (100 ml). This solution was filtered through a pad of 30 g of silica. The eluent was concentrated and the resulting residue was washed with CH ₃ OH (-70°C) to obtain the title compound (1.274 g, 37%) as a beige crystalline solid.

^1H NMR: 7.19 (1H, m), 7.65 (1H, m), 7.95 (1H, d), 8.49 (1H, m), 8.61 (1H, d), 8.85-8.91 (1H, m), 8.92 ( 1H, s); m/z: ES ⁺ MH ⁺ 231.

Intermediate 153: 4-[(3R)-3-Dimethylaminopyrrolidin-1-yl]-6-methoxy-N-(4pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3 -diamine

A mixture of N-[4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl]-4-pyrazolo[1,5a]pyridin-3-ylpyrimidin-2-amine (Intermediate 154 , 440 mg, 0.93 mmol), iron (311 mg, 5.56 mmol), NH4Cl (37.2 mg, 0.70 mmol), ethanol (15 ml) and water (5 ml) were refluxed at for 1.5 hours. After cooling, the mixture was concentrated in vacuo. The resulting residue was triturated with 10% CH3OH in CH ₂ Cl ₂ (20 ml) for 15 minutes and then filtered. The residue was triturated again with 10% CH3OH in CH ₂ Cl ₂ (10 ml) and then filtered. The combined filtrates were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 0-10% methanolic ammonia in CH ₂ Cl ₂ and trituration with diethyl ether gave the title compound (339 mg, 82%) as a yellow solid.

^1H NMR: 1.73-1.83 (1H, m), 2.00-2.10 (1H, m), 2.20 (6H, s), 2.81-2.90 (1H, m), 2.92-3.00 (2H, m), 3.113.16 (1H, m), 3.17-3.24 (1H, m), 3.73 (3H, s), 4.28 (2H, br s), 6.71 (1H, s), 7.07 (1H, td), 7.20 (1H, d) , 7.27 (1H, s), 7.37-7.42 (1H, m), 7.97 (1H, s), 8.30 (1H, d), 8.53 (1H, d), 8.76 (1H, s), 8.79 (1H, d ); m/z: ES ⁺ MH ⁺ 445.33.

Intermediate 154: N-[4-[(3R)-3-Dimethylaminopyrrolidin-1-yl]-2-methoxy-5nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine.

(3R)-N,N-Dimethylpyrrolidin-3-amine (0.166 ml, 1.31 mmol) was added to the suspension of H-(4-fluoro-2methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridine -3-ylpyrimidin-2-amine (Intermediate 155, 415 mg, 1.09 mmol) and DIPEA (0.227 ml, 1.31 mmol) in DMA (3.2 ml) and the mixture was heated at 85°C for 1 Partial purification was achieved by ion exchange chromatography using an SCX column and eluting with 7 M methanol ammonia. Pure fractions were combined and concentrated. Further purification by FCC eluting with 0-7% CH ₃ OH in CH ₂ Cl ₂ gave the title compound (443 mg, 86%) as an orange solid.

^1H NMR: 1.77-1.88 (1H, m), 2.13-2.20 (1H, m), 2.23 (6H, s), 2.75-2.84 (1H, m), 3.14-3.26 (3H, m), 3.433.51 (1H, m), 3.96 (3H, s), 6.58 (1H, s), 7.08 (1H, td), 7.27 (1H, d), 7.34-7.39 (1H, m), 8.24 (1H, s), 8.35 (1H, d), 8.40 (1H, s), 8.49 (1H, d), 8.78 (1H, s), 8.80 (1H, d); m/z: ES ⁺ MH ⁺ 475.31.

Intermediate 155 >(4-Fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3ylpyrimidin-2-amine.

A mixture of 3-(2-chloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine (Intermediate 152, 1.476 g, 6.40 mmol), 4-fluoro-2-methoxy-5-nitroaniline (Intermediate 23 , 1.310 g, 7.04 mmol), p-toluenesulfonic acid monohydrate (1.339 g, 7.04 mmol) and 2-pentanol (45 ml) were heated at 125°C for 22 hours. After cooling, the mixture was filtered. The solid was washed with CH ₃ OH, diethyl ether and then filter dried to obtain a brown solid. The solid was dissolved in CH ₂ Cl ₂ and this solution was washed with sat. NaHCO ₃ (3x), water and brine, then dried (MgSO ₄ ) and concentrated in vacuo. The resulting residue was triturated in boiling CH ₃ CN and then left to cool. The resulting solid was collected by filtration and air-dried to give the title compound (1.29 g, 53%) as a brown solid.

^1H NMR: 4.03 (3H, s), 7.11 (1H, td), 7.37 (1H, d), 7.41 (1H, d), 7.43-7.48 (1H, m), 8.45 (1H, d), 8.51 ( 1H, s), 8.58 (1H, d), 8.82-8.84 (2H, m), 9.00 (1H, d); m/z: ES+MH+ 381.54.

Intermediate 156: 4-(3-Dimethylaminoazetidin-1-yl)-6-methoxy-N-(4-pyrazolo[1,5a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine.

Mixture of >[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3ylpyrimidin-2-amine (Intermediate 157, 355 mg, 0 .77 mmol), iron (258 mg, 4.63 mmol), NH ₄ Cl (30.9 mg, 0.58 mmol), ethanol (12.6 ml) and water (4.2 ml) were refluxed for 1.5 hours. After cooling, the mixture was concentrated in vacuo. The resulting residue was triturated with 10% CH ₃ OH in CH ₂ Cl ₂ (20 ml) for 15 minutes and then the mixture was filtered. The residue was triturated again with 10% CH ₃ OH in CH ₂ Cl ₂ (20 ml) and then filtered. The combined filtrates were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 0-10% methanolic ammonia in CH2Cl2 and trituration with diethyl ether gave the title compound (249 mg, 75%) as a brown solid.

^1H NMR: 2.12 (6H, s), 3.02-3.09 (1H, m), 3.47 (2H, t), 3.71 (3H, s), 3.98 (2H, t), 4.04 (2H, br s), 6.28 (1H, s), 7.05 (1H, td), 7.09 (1H, s), 7.16 (1H, d), 7.36-7.41 (1H, m), 7.93 (1H, s), 8.27 (1H, d), 8.48 (1H, d), 8.74 (1H, s), 8.77 (1H, d); m/z: ES ⁺ MH ⁺ 431.35.

Intermediate 157. >[4-(3-Dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine.

- 75 046985

N,N-dimethylazetidine-3-amine dihydrochloride (Intermediate 26, 227 mg, 1.31 mmol) was added to the suspension of Na(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a ]pyridin-3-ylpyrimidin-2amine (Intermediate 155, 415 mg, 1.09 mmol) and DIPEA (0.755 ml, 4.36 mmol) in DMA (3.2 ml) and the mixture was heated at 85°C for 1 h. The mixture was partially purified by ion exchange chromatography using an SCX column and eluting with 7 M methanolic ammonia. Pure fractions were combined and concentrated in vacuo. Further purification by FCC eluting with 0-7% CH ₃ OH in CH ₂ Cl ₂ gave the title compound (360 mg, 72%) as an orange solid.

^1H NMR: 2.15 (6H, s), 3.12-3.19 (1H, m), 3.74-3.78 (2H, m), 3.95 (3H, s), 4.04-4.09 (2H, m), 6.29 (1H, s ), 7.08 (1H, td), 7.28 (1H, d), 7.36-7.41 (1H, m), 8.26 (1H, s), 8.35 (1H, d), 8.45-8.49 (2H, m), 8.78 ( 1H, s), 8.80 (1H, d); m/z: ES ⁺ MH ⁺ 461.33.

Intermediate 158. N-(2-Dimethylaminoethyl)-5-methoxy-N-methyl-H ⁴ -(4pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,2,4- triamine

Mixture of N-(2-dimethylaminoethyl)-2-methoxy-N-methyl-5-nitro-N(4-pyrazolo[1,5-a]pyridin-3ylpyrimidin-2-yl)benzene-1,4-diamine (Intermediate compound 159, 440 mg, 0.95 mmol), iron (319 mg, 5.71 mmol), NH ₄ Cl (38.2 mg, 0.71 mmol), ethanol (15 ml) and water (5 ml) boiled reflux for 1.5 hours. After cooling, the mixture was concentrated in vacuo. The resulting residue was triturated with 10% CH3OH in CH ₂ Cl ₂ (20 ml) for 15 minutes and then the mixture was filtered. The residue was triturated again with 10% CH3OH in CH ₂ Cl ₂ (20 ml) and then filtered. The combined filtrates were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 0-10% methanolic ammonia in CH2Cl2 and trituration with diethyl ether gave the title compound (321 mg, 78%) as a brown gum.

^1H NMR: 2.18 (6H, s), 2.37 (2H, t), 2.65 (3H, s), 2.91 (2H, t), 3.72 (3H, s), 4.57 (2H, br s), 6.77 (1H , s), 7.07 (1H, td), 7.22 (1H, d), 7.29 (1H, s), 7.37-7.42 (1H, m), 7.97 (1H, s), 8.31 (1H, d), 8.52 ( 1H, d), 8.76 (1H, s), 8.77-8.80 (1H, m); m/z: ES ⁺ MH ⁺ 433.36.

Intermediate 159. Na-(2-Dimethylaminoethyl)-2-methoxy-N-methyl-5-nitro-Na(4pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,4- diamine

>AA-Trimethylethane-1,2-diamine (138 mg, 1.35 mmol) was added to the suspension of Na(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridine-3 -ylpyrimidin-2-amine (Intermediate 155, 428 mg, 1.13 mmol) and DIPEA (0.234 ml, 1.35 mmol) in DMA (3.3 ml) and the mixture was heated at 85°C for 1.5 Partial purification was achieved by ion exchange chromatography using an SCX column and eluting with 7 M methanol ammonia. Pure fractions were combined and concentrated in vacuo. Further purification by FCC eluting with 0-10% CH3OH in CH ₂ Cl ₂ gave the title compound (444 mg, 85%) as an orange oil.

1H NMR: 2.18 (6H, s), 2.50-2.53 (2H, m), 2.87 (3H, s), 3.26-3.30 (2H, m), 3.95 (3H, s), 6.86 (1H, s), 7.09 (1H, td), 7.30 (1H, d), 7.35-7.40 (1H, m), 8.27 (1H, s), 8.37 (1H, d), 8.47-8.51 (2H, m), 8.79 (1H, s ), 8.79-8.82 (1H, m); m/z: ES ⁺ MH ⁺ 463.33.

Intermediate 160: 4-[(3aR,6aR)-5-Methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4b]pyrrol-1-yl]-6-methoxy-N-(4 -pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine.

Mixture of N-[4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-2-methoxy-5nitrophenyl] -4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 161, 190 mg, 0.39 mmol), iron (131 mg, 2.34 mmol), NH ₄ Cl (14 .62 mg, 0.27 mmol), ethanol (6 ml) and water (2 ml) were refluxed for 4 hours and then stirred at room temperature. during the night. By ion exchange chromatography using an SCX column and eluting with 7N. Partial purification was achieved with methanol ammonia. The corresponding fractions were then concentrated in vacuo on silica. As a result of purification by FCC eluting with 0-5% 7N. methanol ammonia in CH ₂ Cl ₂ obtained contaminated material. Fractions containing the desired product were pooled and further purified by FCC, eluting with 0-2.5% 7N. methanolic ammonia in CH ₂ Cl ₂ to obtain the title compound (100 mg, 56%); m/z: ES ⁺ MH ⁺ 457.21.

Intermediate 161. N-[4-[(3aR,6aR)-5-Methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1 -yl]-2-methoxy -5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine.

DIPEA (0.343 mL, 1.97 mmol) was added to a suspension of N(4-fluoro-2-methoxy-5-nitrophenyl)-4pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 155, 300 mg, 0.79 mmol) and (3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-b]pyrrole (Intermediate 37, 109 mg, 0.87 mmol) in 2,2,2-trifluoroethanol (5 ml) and the mixture was heated under microwave conditions at 140°C for 1 hour. After cooling, the mixture was partially purified by ion exchange chromatography using an SCX column and eluting 7 M methanol ammonia. The corresponding fractions were then concentrated in vacuo on silica. As a result of additional purification by FCC eluting with 0-4% 7N. methanolic ammonia in CH2Cl2 gave the title compound (198 mg, 52%) as a slightly contaminated orange/red solid which was used without further purification.

- 76 046985 ¹ H NMR (CDCI3): 1.89 (1H, dd), 2.06-2.18 (1H, m), 2.21 (3H, s), 2.31 (1H, dd), 2.47 (2H, ddd), 2.65 (1H , t), 2.99-3.10 (1H, m), 3.26 (1H, g), 3.51-3.60 (1H, m), 3.98 (3H, s), 4.39-4.46 (1H, m), 6.46 (1H, s ), 6.93 (1H, td), 7.04 (1H, d), 7.38 (1H, s), 7.43 (1H, ddd), 8.36 (1H, d), 8.46 (1H, s), 8.52 (1H, m) , 8.58 (1H, m), 8.98 (1H, s); m/z: ES+MH+ 487.15.

Intermediate 162 )benzene-1,3-diamine.

A mixture of N[2-methoxy-4-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-5-nitrophenyl]-4-pyrazolo[1,5a]pyridin-3-ylpyrimidin-2- amine (Intermediate 163, 404 mg, 0.83 mmol), iron (278 mg, 4.98 mmol), NH ₄ Cl (33.3 mg, 0.62 mmol), ethanol (15 ml) and water (5 ml) was refluxed for 1.5 hours. After cooling, the mixture was filtered and the residues were washed with a 1:10 mixture of CH ₃ OH-CH ₂ Cl ₂ (20 ml). The combined filtrates were concentrated in vacuo on silica. Purification by FCC eluting with 1-10% methanol ammonia in CH ₂ Cl ₂ gave the title compound (338 mg, 89%) as a yellow solid.

1H NMR: 1.72 (2H, dt), 2.11 (2H, dd), 2.42 (3H, s), 2.66 (2H, t), 3.63 (2H, d), 3.72 (3H, s), 3.87 (2H, d ), 4.03 (2H, s), 6.29 (1H, s), 7.06 (1H, td), 7.10 (1H, s), 7.16 (1H, d), 7.35-7.42 (1H, m), 7.93 (1H, s), 8.27 (1H, d), 8.52 (1H, d), 8.74 (1H, s), 8.77 (1H, t); m/z: ES+MH+ 457.36.

Intermediate 163. N[2-Methoxy-4-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-5nitrophenyl]-4-pyrazolo[1,5-3]pyridin-3-ylpyrimidine -2-amine

8-Methyl-2,8-diazaspiro[3.4]octane (Intermediate 47, 133 mg, 0.88 mmol) was added to the suspension of Na(4-fluoro-2-methoxy-5-nitrophenyl)-4-(pyrazolo[1 ,5-a]pyridin-3-yl)-pyrimidin-2-amine (Intermediate 155, 280 mg, 0.74 mmol) and DIPEA (0.153 ml, 0.88 mmol) in DMA (3 ml) and the mixture was heated at 100°C for 1 hour. The mixture was then partially purified by ion exchange chromatography using an SCX column eluting with 7 M methanol ammonia. Pure fractions were combined and concentrated in vacuo. Further purification by FCC eluting with 1-8% CH3OH in CH ₂ Cl ₂ gave the title compound (300 mg) as an orange dry film.

1H NMR: 1.71 (2H, dt), 2.05 (2H, dd), 2.40 (3H, s), 2.67 (2H, t), 3.75 (2H, d), 3.95 (3H, s), 4.11 (2H, d ), 6.31 (1H, s), 7.09 (1H, td), 7.28 (1H, d), 7.35-7.41 (1H, m), 8.25 (1H, s), 8.36 (1H, d), 8.47 (1H, s), 8.50 (1H, d), 8.79 (1H, s), 8.79-8.82 (1H, m); m/z: ES ⁺ MH ⁺ 487.30.

Intermediate 164 4-[(3R)-3-Dimethylaminopyrrolidin-1-yl]-N-[4-(1H-indol-3yl)pyrimidin-2-yl]-6-methoxybenzene-1,3-diamine.

To a stirred mixture of N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}4-(N-indol-3-yl)pyrimidin-2-amine (Intermediate 165 , 286 mg, 0.60 mmol), iron (202 mg, 3.62 mmol), NH ₄ Cl (22.6 mg, 0.42 mmol) and ethanol (24 ml), water (4 ml) was added. The resulting mixture was stirred at 105°C for 3 hours and then filtered through diatomaceous earth (Celite™) and concentrated in vacuo. Partial purification by ion exchange chromatography using an SCX column and eluting with 0.35 M methanolic ammonia gave the title compound (312 mg, 116%) as a brown gum which was used without further purification.

1H NMR: 2.13 (2H, d), 2.32 (2H, d), 2.80 (6H, d), 2.87-2.98 (2H, m), 3.19 (2H, d), 3.77 (3H, s), 6.74 (1H , s), 7.17 (4H, ddd), 7.46 (1H, d), 7.56 (1H, s), 7.77 (1H, s), 8.28 (2H, dd), 8.43 (1H, d), 11.76 (1H, s); m/z: ES ⁺ MH ⁺ 444.

Intermediate 165. N-{4-[(3R)-3-Dimethylaminopyrrolidin-1-yl]-2-methoxy-5nitrophenyl}-4-(N-indol-3-yl)pyrimidin-2-amine.

(3R)-N,N-Dimethylpyrrolidin-3-amine (92 mg, 0.81 mmol) was added to the mixture of N(4-fluoro-2-methoxy5-nitrophenyl)-4-(N-indol-3-yl)pyrimidine -2-amine (Intermediate 68, 404 mg, 0.73 mmol) and DIPEA (0.256 ml, 1.46 mmol) in DMA (3 ml). The mixture was then heated under microwave conditions at 140° C. for 0.5 h. Partial purification was achieved by ion exchange chromatography using an SCX column (20 g) and eluting with 0.35 M methanolic ammonia. The appropriate fractions were combined and concentrated in vacuo to give an orange/brown gum. This resin was triturated with ethanol (15 ml) to obtain a solid, which was collected by filtration and dried under vacuum to obtain the title compound (291 mg, 84%) as an orange solid.

1H NMR: 1.82 (1H, dt), 2.12-2.20 (1H, m), 2.22 (6H, s), 2.73-2.83 (1H, m), 3.12-3.22 (2H, m), 3.22-3.27 (1H, m), 3.41-3.51 (1H, m), 3.97 (3H, s), 6.58 (1H, s), 7.07 (1H, t), 7.18 (1H, t), 7.26 (1H, d), 7.45 (1H , d), 8.00 (1H, s), 8.28-8.31 (2H, m), 8.35 (1H, d), 8.57 (1H, s), 11.78 (1H, s); m/z: ES+MH+ 474.30.

Intermediate 166. 4-(3-Dimethylaminoazetidin-1-yl)-N[4-(III-indol-3yl)pyrimidin-2-yl]-6-methoxybenzene-1,3-diamine.

To a mixture of N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1H-indol-3 yl)pyrimidin-2-amine (Intermediate 167, 240 mg, 0 .52 mmol), iron (175 mg, 3.13 mmol), NH ₄ Cl (19.56 mg, 0.37 mmol) and ethanol (24 ml), water (4 ml) was added. The resulting mixture

- 77 046985 was stirred at 105°C for 3 hours and then filtered through diatomaceous earth (Celite™). The filtrate was concentrated in vacuo and partially purified by ion exchange chromatography using an SCX column and eluting with 0.35 M methanol ammonia. The appropriate fractions were combined and concentrated in vacuo to give the title compound (241 mg, 107%) as a brown gum which was used without further purification; m/z: ES+MH+ 430.

Intermediate 167. N[4-(3-Dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4(1H-indol-3-yl)pyrimidin-2-amine.

H^dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 140 mg, 0.81 mmol) was added to the suspension of Na(4-fluoro-2-methoxy-5-nitrophenyl)-4-(III-indol-3-yl) pyrimidin-2-amine (Intermediate 68, 406 mg, 0.74 mmol) and DIPEA (0.514 ml, 2.94 mmol) in DMA (3 ml). The mixture was heated under microwave conditions at 140° C. for 0.5 h. The mixture was then partially purified by ion exchange chromatography using an SCX column (20 g) and eluting with 0.35 M methanol ammonia. The appropriate fractions were combined and concentrated in vacuo to give an orange/brown gum. This resin was triturated with ethanol (15 ml) to obtain a solid, which was collected by filtration and dried under vacuum to obtain the title compound (245 mg, 72%) as an orange solid.

^1H NMR: 2.15 (6H, s), 3.17 (1H, dd), 3.76 (2H, dd), 3.97 (3H, s), 4.03-4.10 (2H, m), 6.29 (1H, s), 7.08 ( 1H, t), 7.14-7.21 (1H, m), 7.27 (1H, d), 7.45 (1H, d), 8.01 (1H, s), 8.28-8.37 (3H, m), 8.64 (1H, s) , 11.79 (1H, s); m/z: ES ⁺ MH ⁺ 460.32.

Intermediate 168. N-(2-Dimethylaminoethyl)-C4-[4-(III-indol-3-yl)pyrimidin-2yl]-5-methoxy-N-methylbenzene-1,2,4-triamine

O

Water (4 ml) was added in one portion to the mixture of N-(2-dimethylaminoethyl)-N[4-(III-indol-3yl)pyrimidin-2-yl]-2-methoxy-N-methyl-5-nitrobenzene-1, 4-diamine (Intermediate 169, 270 mg, 0.59 mmol), iron (196 mg, 3.51 mmol), NH ₄ Cl (21.9 mg, 0.41 mmol) and ethanol (24 ml). The resulting mixture was heated at 105°C for 3 hours, then filtered through diatomaceous earth (Celite™). The filtrate was concentrated in vacuo and then partially purified by ion exchange chromatography using an SCX column and eluting with 0.35 M methanolic ammonia. The appropriate fractions were combined and concentrated in vacuo to give the title compound (244 mg, 97%) as a brown solid which was used without further purification.

1H NMR: 2.18 (6H, s), 2.37 (2H, s), 2.64 (3H, s), 2.90 (2H, s), 3.76 (3H, s), 6.77 (1H, s), 7.03-7.26 (3H , m), 7.46 (1H, d), 7.52 (1H, s), 7.74 (1H, s), 8.18-8.35 (2H, m), 8.42 (1H, d), 11.72 (1H, s); m/z: ES ⁺ MH ⁺ 432.

Intermediate 169. N-(2-Dimethylaminoethyl)-N[4-(III-indol-3-yl)pyrimidin-2-yl]2-methoxy-N-methyl-5-nitrobenzene-1,4-diamine

^,^^ ² -Trimethylethane-1,2-diamine (83 mg, 0.82 mmol) was added to the mixture of Na(4-fluoro-2-methoxy-5nitrophenyl)-4-(III-indol-3-yl)pyrimidine -2-amine (Intermediate 68, 409 mg, 0.74 mmol), DIPEA (0.259 ml, 1.48 mmol) and DMA (3 ml). The resulting mixture was heated under microwave conditions at 140° C. for 0.5 h. Partial purification was achieved by ion exchange chromatography using an SCX column (20 g) and eluting with 0.35 M methanolic ammonia. The appropriate fractions were concentrated in vacuo to give an orange/brown gum. This resin was triturated with ethanol (15 ml) to obtain a solid, which was collected by filtration and dried under vacuum to obtain the title compound (275 mg, 80%) as an orange solid.

1H NMR: 2.18 (6H, s), 2.45-2.55 (2H, m), 2.87 (3H, s), 3.25-3.30 (2H, m), 3.97 (3H, s), 6.87 (1H, s), 7.08 (1H, t), 7.18 (1H, t), 7.29 (1H, d), 7.46 (1H, d), 8.03 (1H, s), 8.33 (3H, dd), 8.66 (1H, s), 11.80 ( 1H, s); m/z: ES ⁺ MH ⁺ 462.34.

Intermediate 170. tert-Butyl-No[2-[[5-methoxy-4-[[4-(1-methylindol-3-yl)pyrimidin2-yl]amino]-2-(prop-2-enoylamino)phenyl ]-methylamino]ethyl]-Nmethylcarbamate.

- 78 046985

Acryloyl chloride (0.069 ml, 0.85 mmol) in CH2C12 (2.5 ml) was added dropwise over 5 min to a solution of tert-butyl-N-[2-[[2-amino-5-methoxy-4-[[ 4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]methylamino]ethyl]-K-methylcarbamate (Intermediate 171, 377 mg, 0.71 mmol) and DIPEA (0.234 ml, 1. 42 mmol) in CH ₂ Cl ₂ (8 ml) cooled in an ice/methanol bath. The mixture was stirred for 0.5 hours. The mixture was then diluted with 10% CH3OH in CH ₂ Cl ₂ . The resulting solution was washed with sat. NaHCO ₃ , dried (MgSO ₄ ) and then concentrated in vacuo. Purification by FCC eluting with 0-3% CH3OH in CH ₂ Cl ₂ gave the title compound (325 mg, 78%) as a yellow foam.

1H NMR: 1.38 (9H, s), 2.71 (3H, s), 2.77 (3H, s), 3.00 (2H, t), 3.34 (2H, t), 3.88 (3H, s), 3.91 (3H, s ), 5.735.78 (1H, m), 6.27 (1H, dd), 6.67 (1H, dd), 6.99 (1H, s), 7.17 (1H, t), 7.21-7.27 (2H, m), 7.53 ( 1H, d), 7.87 (1H, s), 8.26 (1H, d), 8.33 (1H, d), 8.62 (1H, s), 8.99 (1H, s), 9.10 (1H, s); m/z: ES+MH+ 584.73.

Intermediate 171. tert-Butyl-No[2-[[2-amino-5-methoxy-4-[[4-(1-methylindol-3yl)pyrimidin-2-yl]amino]phenyl]-methylamino]ethyl] -No methyl carbamate.

tert-Butyl-N[2-[[5-methoxy-4-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]-2-nitrophenyl]methylamino]ethyl]-Nmethylcarbamate ( Intermediate 172, 428 mg, 0.76 mmol), iron (255 mg, 4.57 mmol) and NH4Cl (30.6 mg, 0.57 mmol) in ethanol (16 ml) and water (5.33 ml) reflux for 1.5 h (heat lock 100°C) and then the mixture was cooled and concentrated in vacuo. The resulting residue was triturated in 10% CH ₃ OH/CH ₂ Cl ₂ (30 ml) and filtered. The residue was triturated again with 10% CH ₃ OH/CH ₂ Cl ₂ (30 ml) and filtered. The combined filtrates were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 0-5% CH3OH in CH2Cl2 gave the title compound (380 mg, 94%) as a light brown foam.

^1H NMR: 1.41 (9H, s), 2.64 (3H, s), 2.80 (3H, s), 2.95 (2H, t), 3.34 (2H, t), 3.77 (3H, s), 3.89 (3H, s), 4.40 (2H, s), 6.78 (1H, s), 7.14-7.20 (2H, m), 7.23-7.27 (1H, m), 7.52 (1H, d), 7.55 (1H, s), 7.75 (1H, s), 8.28 (1H, d), 8.29 (1H, s), 8.42 (1H, d); m/z: ES+MH+ 532.37.

Intermediate 172. tert-Butyl-No[2-[[5-methoxy-4-[[4-(1-methylindol-3-yl)pyrimidin2-yl]amino]-2-nitrophenyl]-methylamino]ethyl]- No. methyl carbamate.

tert-Butyl-Namethyl-Na(2-methylaminoethyl)carbamate (Intermediate 173, 300 mg, 1.59 mmol) was added to a suspension of Na(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1- methylindol-3yl)pyrimidin-2-amine (Intermediate 129, 522 mg, 1.33 mmol) and DIPEA (0.462 ml, 2.65 mmol) in DMA (5 ml). The mixture was heated under microwave conditions at 100°C for 4 hours. The mixture was then diluted with EtOAc and washed with water (5x), brine, dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 0-2% CH ₃ OH in CH ₂ Cl ₂ and trituration with diethyl ether gave the title compound (431 mg, 58%) as an orange solid.

1H NMR: 1.37 (9H, s), 2.79 (3H, s), 2.88 (3H, s), 3.29-3.36 (2H, m), 3.39-3.44 (2H, m), 3.89 (3H, s), 3.99 (3H, s), 6.85 (1H, d), 7.14 (1H, t), 7.21-7.28 (2H, m), 7.53 (1H, br d), 8.04 (1H, s), 8.31-8.38 (3H, m), 8.72 (1H, br s); m/z: ES+MH+ 562.35.

Intermediate 173. tert-Butyl-Nmethyl-N(2-methylaminoethyl)carbamate.

A solution of di-tert-butyl dicarbonate (4.95 g, 22.69 mmol) in CH ₂ Cl ₂ (240 ml) was added dropwise to a stirred solution of N-dimethylethane-1,2-diamine (4 g, 45.38 mmol) in CH ₂ Cl ₂ (80 ml) for a period of 20 hours. The resulting mixture was stirred at room temperature. for 3 hours. Then the mixture was successively washed with sat. Na ₂ CO ₃ (2x100 ml), water (50 ml) and sat. brine (50 ml). The organic solution was dried (MgSO ₄ ) and concentrated in vacuo. Purification by FCC eluting with 0-10% CH3OH in CH2Cl2 provided the title compound (2.177 g, 51%) as a pale yellow oil.

1H NMR: 1.40 (9H, s), 2.28 (3H, s), 2.57 (2H, t), 2.79 (3H, s), 3.20 (2H, t).

Intermediate 174. 3-Chloro-No[2-[2-dimethylaminoethyl(methyl)amino]-4-methoxy-5-[[4(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl] propanamide

To a stirred suspension of ^-(2-dimethylaminoethyl)-5-methoxy-^-methyl-^-[4-(1-methylindol3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine (Intermediate 175 , 33 g, 62.29 mmol) and K ₂ CO ₃ (6.09 g, 43.6 mmol) in acetone (300 ml) was added 3-chloropropanoyl chloride (9.78 g, 74.74 mmol) at -50° WITH. The resulting mixture was heated to -20°C and stirred for 0.5 h. CH3OH (27.75 ml) and a solution of NaOH (2.24 g, 56.06 mmol in 300 ml water) were added. The resulting mixture was stirred during

- 79 046985 3-4 hours at room temperature. The solid was collected by filtration and dried at 50°C to give the title compound (32.5 g, 95%).

^1H NMR (CDClj): 2.95 (2H, t), 3.04 (6H, d), 3.50 (3H, s), 3.63 (2H, s), 3.81 (2H, t), 4.01 (6H, s), 4.33 -4.37 (2H, m), 7.33-7.42 (3H, m), 7.47 (1H, t), 7.51-7.55 (1H, m), 8.11-8.21 (3H, m), 8.48 (1H, s), 8.87 (1H, s), 9.17 (1H, s); m/z: ES ⁺ MH ⁺ 536.24.

Intermediate 175. ^-(2-Dimethylaminoethyl)-2-methoxy-H ⁴ -methyl-N-[4-(1methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-1,4-diamine

To a stirred solution of K-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3yl)pyrimidin-2-amine (Intermediate 176, 65 g, 160.28 mmol) and K,K ',K'-trimethylethane-1,2-diamine (19.65 g, 192.3 mmol) in DMA (630 ml) was added N-ethyl-K-isopropylpropan-2-amine (26.93 g, 208.4 mmol) at k.t. The resulting mixture was stirred at 85°C for 5-6 hours, then cooled to room temperature. Water (630 ml) was then added and the mixture was stirred for 3-4 hours. The solid material was collected by filtration, washed with water (315 ml) and dried at 50°C for 12 hours to obtain the title compound (79.4 g, 96%) as an orange solid.

^1H NMR (CDClj): 2.29 (6H, s), 2.60 (2H, t), 2.93 (3H, s), 3.31 (2H, t), 3.96 (3H, s), 4.00 (3H, s), 6.69 (1H, s), 7.21 (1H, d), 7.30-7.38 (2H, m), 7.43 (1H, d), 7.56 (1H, s), 8.18 (1H, d), 8.30 (1H, s), 8.41 (1H, d), 9.59 (1H, s); m/z: ES ⁺ MH ⁺ 476.23.

Intermediate 176. K-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3yl)pyrimidin-2-amine

^.0

1,4-Dioxane (585 ml) was added to a mixture of 3-(2-chloropyrimidin-4-yl)-1-methyl-indole (Intermediate 177, 50 g, 160.04 mmol), 4-fluoro-2-methoxy -5-nitroaniline (38.03 g, 192.04 mmol) and p-toluenesulfonic acid monohydrate (37.09 g, 192.04 mmol) at r.t. The resulting mixture was stirred at 85°C for 3 hours. After cooling to room temperature. the mixture was quenched with 23% aqueous ammonia (39.59 mL, 480.1 mmol) and water (195 mL, 510.1 mmol) and a solid precipitated. The resulting suspension was stirred at room temperature. for 3-4 hours. The solid was collected by filtration and dried at 50°C in vacuo for 12 hours to obtain the title compound (74.6 g, 85%) as a yellow solid.

^1H NMR (CDClj): 4.01 (6H, s), 6.90 (1H, d), 7.37-7.48 (4H, m), 8.05-8.12 (2H, m), 8.43 (1H, s), 8.90 (1H, s), 9.34 (1H, s); m/z: ES ⁺ MH ⁺ 394.12.

Intermediate 177: 3-(2-Chloropyrimidin-4-yl)-1-methylindole.

To a stirred solution of 2,4-dichloropyrimidine (70.5 g, 463.76 mmol) in dimethoxyethane (900 ml) was added FeCl ₃ (77.16 g, 459.12 mmol) and 1-methylindole (68.28 g) at 60°C. The resulting mixture was stirred overnight at 60°C. After cooling by adding methanol (345 ml) and water (900 ml), a solid precipitated. The resulting suspension was stirred for 3 hours. The solid was collected by filtration, washed with CH3OH (1.38 L) and dried at 50°C overnight to give the title compound (138.7 g, 81.5%) as violet solid matter.

^1H NMR ( _CDCl3 ) 3.89 (3H, s), 7.36-7.41 (3H, m), 7.49 (1H, s), 7.96 (1H, s), 8.34 (1H, s), 8.45 (1H, s) ; m/z: ES ⁺ MH ⁺ 244.05.

Useful crystalline polymorphic forms of K-(2-(2-dimethylaminoethyl-methylamino}-4methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide ( referred to herein as Compound X) and its mesylate salt (referred to herein as Mesylate Salt Y).

Polymorphic Form A of Compound X.

The initially formed Compound X was found to be an amorphous solid. Then, taking some of this amorphous Compound X (about 20 mg) and suspending it in cyclohexane (about 2 ml) at 50°C and stirring using magnetic

- 80 046985 stirring for approximately 4 days, a crystalline polymorphic Form A of Compound X was obtained. The sample was then allowed to cool, the cap was removed from the vial, and the sample was left to dry at ambient conditions to obtain Form A of Compound X. Powder X-ray diffraction pattern of Form A Compound X is shown in FIG. 1. The DSC thermogram of Form A of Compound X is shown in FIG. 2, which shows an initial event with an onset at 35.1°C and a peak at 50.1°C, followed by a melting endotherm with an onset at 80.2°C and a peak at 88.3°C.

Polymorphic form B of Compound X.

The initially formed Compound X was found to be an amorphous solid. Then, taking some of this amorphous Compound X (approximately 20 mg) and dissolving it in the minimum required amount of EtOAc to achieve complete dissolution, the crystalline polymorphic Form B of Compound X was obtained. This solution was then allowed to evaporate to dryness under ambient conditions to obtain Form B of Compound X X. The X-ray powder diffraction pattern of Form B of Compound X is shown in FIG. 3. The DSC thermogram of Form B of Compound X is shown in FIG. 4, which shows a melting endotherm with an onset at 94.1°C and a peak at 113.6°C.

Polymorphic form C of Compound X.

The initially formed Compound X was found to be an amorphous solid. Then, by taking a quantity of this amorphous Compound X (about 20 mg) and dissolving it in the minimum amount of diethyl ether required to achieve complete dissolution, the crystalline polymorph Form C of Compound X was obtained. This solution was then allowed to evaporate to dryness under ambient conditions to obtain the form C of Compound X. The powder X-ray diffraction pattern of Form C of Compound X is shown in FIG. 5. The DSC thermogram of Form C of Compound X is shown in FIG. 6, which shows a melting endotherm with an onset at 91.1°C and a peak at 103.8°C.

Polymorphic Form D of Compound X.

Polymorph Form D of Compound X, which was believed to be the crystalline monohydrate form of Compound X, was prepared by the method described above for Example 28 - Alternative Syntheses 1 and 2. The powder x-ray diffraction pattern of Form D of Compound X is depicted in FIG. 7. The DSC thermogram of Form C of Compound X is shown in FIG. 8, which shows a melting endotherm with an onset at 108.8°C and a peak at 117.7°C. Thermogravimetric analysis showed a mass loss of approximately 3.3%, which indicates the monohydrate form (theoretical monohydrate means 3.5%). The TGA thermogram is shown in Fig. 9.

Polymorphic form E of Compound X.

Polymorph Form E of Compound X, which was believed to be the 1,25-stoichiometric hydrate form of Compound X, was prepared by suspending Compound X [154 g prepared as described for Example 28 (using acryloyl chloride)] in a mixture of methanol (150 ml) and water (600 ml). 10 g of Compound X (Form D) was added and the suspension was stirred at room temperature. within 4 days. The resulting solid was then collected by filtration and washed with water and left to dry. The X-ray powder diffraction pattern of Form E of Compound X is shown in FIG. 10. The DSC thermogram of Form E of Compound X is shown in FIG. 11, which shows an initial event with an onset at 66.1°C and a peak at 77.2°C, followed by an additional event with an onset at 93.6°C and a peak at 101.5°C, and a subsequent melting endotherm with an onset at 130.9°C and peak at 135.3°C. Thermogravimetric analysis showed a mass loss of approximately 4.7%, which suggests that the hydrate form is equivalent to a 1.25-stoichiometric hydrate (theoretical 1.25 hydrate means 4.3%). The TGA thermogram is shown in Fig. 12.

Polymorphic form F of Compound X.

Polymorph Form F of Compound X, which was believed to be the 0.25 stoichiometric hydrate form of Compound X, was prepared by drying a quantity of Form E of Compound X in a vacuum oven at room temperature. to constant mass. The X-ray powder diffraction pattern of Form F of Compound X is shown in FIG. 13. The DSC thermogram of Form F of Compound X is shown in FIG. 14, which shows an initial event with an onset at 80.9°C and a peak at 92.8°C, followed by a melting endotherm with an onset at 130.7°C and a peak at 135.7°C. Thermogravimetric analysis showed a mass loss of approximately 0.7%, which suggests that the partially hydrated form is equivalent to a 0.25 stoichiometric hydrate (theoretical 0.25 hydrate means 0.89%). The TGA thermogram is shown in Fig. 15.

Polymorphic form K of Compound X.

This polymorphic form of Compound X was prepared by the following method.

A solution of acryloyl chloride (0.026 L, 318.48 mmol) in CH ₂ Cl ₂ (290 ml) was added dropwise over 25 min to a stirred suspension of N-(2-(dimethylamino)ethyl)-5-methoxy-N-methyl-H ⁴ -(4-(1-methyl-Shindol-3-yl)pyrimidin-2-yl)benzene-1,2,4-triamine (129 g, 289.52 mmol) in CH ₂ Cl ₂ (2.9 L ), which was cooled to -5°C. The addition is exothermic, but the mixture was not allowed to warm more than 1°C during the addition. The resulting mixture was stirred at -5°C for 2 hours. Then drop by drop

- 81 046985 added cold sat. NaHCO3 solution (1 l), maintaining the temperature below -2°C. The mixture was then left to warm to room temperature. The phases were separated and the resulting organic solution was washed with water (100 ml) and saturated brine (100 ml). The solution was then dried (MgSO ₄ ) and concentrated in vacuo. The residue was dissolved in 5% CH3OH in CH ₂ Cl ₂ (60 ml) and then filtered. The filtered solution was purified by FCC eluting with 5% CH3OH in CH ₂ Cl ₂ and the pure fractions were combined and concentrated to give impure Compound X as a brown gum (96 g). Further purification by chiral preparative HPLC provided a sample of Compound X, which was suspended in CH3OH (50 mL). Not all Compound X was able to dissolve. Water (250 ml) was then added and the resulting mixture was suspended overnight with stirring using a magnetic stirrer. The resulting solid was then collected by filtration and dried in a vacuum oven over the weekend to obtain 16.2 g of Compound X in the polymorphic form defined herein as Form K.

1H NMR: 2.20 (6H, s), 2.28 (2H, m), 2.71 (3H, s), 2.88 (2H, m), 3.85 (3H, s), 3.90 (3H, s), 5.76 (1H, d ), 6.27 (1H, d), 6.43 (1H, m), 7.03 (1H, s), 7.15 (1H, m), 7.22 (2H, m), 7.51 (1H, d), 7.87 (1H, s) , 8.23 (1H, m), 8.33 (1H, m), 8.68 (1H, s), 9.18 (1H, s), 10.16 (1H, s).

The X-ray powder diffraction pattern of Form K of Compound X is shown in FIG. 16. A DSC thermogram of Form K of Compound X is shown in FIG. 17, which shows a melting endotherm with an onset at 129.3°C and a peak at 133.4°C.

Polymorphic form A of Mesylate Salt Y.

Polymorph Form A of Mesylate Salt Y was prepared as previously described (Example 28A, Procedure 3). The powder X-ray diffraction pattern of Form A of Mesylate Salt Y is shown in FIG. 18. The DSC thermogram of Form A of Mesylate Salt Y is shown in FIG. 19, which shows an initial event with an onset at 28.1°C and a peak at 62.2°C, followed by a melting endotherm with an onset at 258.8°C and a peak at 262.0°C.

Polymorphic form B of Mesylate Salt Y.

Polymorph Form B of Mesylate Salt Y was prepared as described previously (Example 28A, Procedures 1 and 2). The powder X-ray diffraction pattern of Form B of Mesylate Salt Y is shown in FIG. 20. The DSC thermogram of Form B of Mesylate Salt Y is shown in FIG. 21, which shows a melting endotherm with an onset at 245.0°C and a peak at 246.5°C.

Claims (6)

1. A pharmaceutical composition having the activity of an inhibitor of the L858R EGFR mutant, and/or the T790M EGFR mutant, and/or the EGFR mutant with a deletion in exon 19, containing a polymorphic form of the mesylate salt >(2-{2-dimethylaminomethyl-methylamino}-4-methoxy -5-{[4-(1-methylindol-3yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide, which has a powder X-ray diffraction pattern with characteristic peaks at 2-theta values of 7, 2; 8.6; 9.5; 10.4; 15.3; 16.4; 18.8; 22.1; 25.7 and 26.1°, where the stated values may differ by ±0.2° 2-theta measured using CuKa radiation. 2. Use of the polymorphic form of the mesylate salt >(2-{2-dimethylaminomethyl-methylamino}-4methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2- enamide, which has a powder X-ray diffraction pattern with characteristic peaks at 2-theta values of 7.2; 8.6; 9.5; 10.4; 15.3; 16.4; 18.8; 22.1; 25.7 and 26.1°, where the indicated values may differ by ±0.2° 2-theta, measured using CuKa radiation, as an inhibitor of the L858R EGFR mutant, and/or the T790M EGFR mutant, and/or the EGFR mutant with deletion in exon 19. 3. Use of the polymorphic form of the mesylate salt >(2-{2-dimethylaminomethyl-methylamino}-4methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2- enamide, which has a powder X-ray diffraction pattern with characteristic peaks at 2-theta values of 7.2; 8.6; 9.5; 10.4; 15.3; 16.4; 18.8; 22.1; 25.7 and 26.1°, where the indicated values may differ by ±0.2° 2-theta, measured using CuKa radiation, in the treatment of cancer. 4. Use according to claim 3, wherein the cancer is non-small cell lung cancer. 5. Use of the polymorphic form of the mesylate salt >(2-{2-dimethylaminomethyl-methylamino}-4methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2- enamide, which has a powder X-ray diffraction pattern with characteristic peaks at 2-theta values of 7.2; 8.6; 9.5; 10.4; 15.3; 16.4; 18.8; 22.1; 25.7 and 26.1°, where the indicated values may differ by ±0.2° 2-theta, measured using CuKa radiation, for the manufacture of a drug for the treatment of cancer. 6. Use according to claim 5, wherein the cancer is non-small cell lung cancer.