ZA200505564B

ZA200505564B - 4-aminopyrimidine-5-one

Info

Publication number: ZA200505564B
Application number: ZA200505564A
Authority: ZA
Inventors: Bartkovitz David Joseph; Ding Qingjie; Lovey Allen John; Mullin Jr John Guilfoyle; Wovkulich Peter Michael; Chu Xin-Jie; Jiang Nan; Moliterni John Anthony; Vu Binh Thanh
Original assignee: Hoffmann La Roche
Priority date: 2003-02-10
Filing date: 2005-07-11
Publication date: 2007-01-31
Also published as: CN101044121A; CO5590920A2

Description

-1- SE

N y 4-Aminopyrimidine-5-one

The present invention relates to novel 4-aminopyrimidine-5-one derivatives of the formula

NH, O

NE R2

M 2 i) N 1

R LL wherein 5s R' isselected from the group consisting of heterocycle and lower alkyl-heterocycle, wherein the heterocycle moiety in both instances optionally may be substituted by up to four substituents independently selected from

H, lower alkyl, : lower alkyl substituted by oxo, OR"?, CO,R'%, NRR®, S(O),RY or

C(O)NRR’,

COR,

CORY, a

CORY, :

C(O)NRPR™,

S(O)aR", 0X0, . OR", or

NR°R%; ’ aryl; aryl substituted by

H,

-2- CL © -S(0)wR”, NR°RS, carbonyl, carbonyl substituted by lower alkyl, OR? or NR’R®, } 5 lower alkyl, : : lower alkyl substituted by OR! or NR°RS,

OR®, or

Halogen; cycloalkyl; cycloalkyl substituted by OR’,NR°R® or $(O)aR" ; lower alkyl; and lower alkyl substituted by

NR’RS,

NR!'SOR",

COzR",

S(0)aR", heterocycle, heterocycle substituted by lower alkyl,

CO,R" or

SOR", heteroaryl, heteroaryl substituted by lower alkyl,

COR", or : SOR”, aryl, and aryl substituted by : lower alkyl, halogen,

NR°R’,

COR" or

COR};

-3- SS

R? is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocycle, wherein each may be substituted by up ) to four substituents independently selected from the group consisting of lower alkyl, ’ 5 lower alkyl substituted by halogen or OR", halogen,

OR"

NO,

CN,

NR’RS,

S(0),-R’, and

SO,-NR'*RY;

R® and R® are each independently selected from the group consisting of lower alkyl; lower alkyl substituted by oxo, CO;R'?, OR'2, NR" R™, C(O)NR"R** , SOR",

NSO,R'"?, heteroaryl, heterocycle, or heterocycle substituted by oxo; cycloalkyl; cycloalkyl substituted by CO.R'Z, ORY, NRPR'*, C(O)NR"R™ or SOR aryl aryl substituted by NR¥R', OR'?, COR", C(O)NR"R' , SO,R", halogen, lower : alkyl, or lower alkyl substituted by halogen, OR", oxo, CO:R'%, C(O)NR"R™ or

NRPPR'® 50:R"; : 25 COR"

COR'* and

OR"

Ro. ©) ~ op AO

- or alternatively, -NR°R® can form a ring having 3 to 7 ring atoms, said ring optionally including one or more additional N or O ring atoms or the group SO,, and optionally being substituted by OH, oxo, NR'’R", lower alkyl and lower alkyl substituted by OR'%

R’ is selected from the group consisting of

H; lower alkyl; lower alkyl substituted by OR'?, CO,R'%, NR’RS, or C(O)NRR® i halogen; 0X0; Co aryl; aryl substituted by up to three substituents independently selected from lower alkyl, halogen and NR’R® cycloalkyl; cycloalkyl substituted by OH, oxo, or NH, :

SO,R' and

COR";

R® is selected from the group consisting of :

H; h lower alkyl; lower alkyl substituted by NR’R% . heterocycle; and heterocycle substituted by lower alkyl, COR"? or SOR:

R’ is selected from the group consisting of

H; and lower alkyl; - 25° RY is selected from the group consisting of

-5- oo oo : : lower alkyl; aryl; and aryl substituted by halogen or NR’R®

R" is selected from the group consisting of

H; lower alkyl; and lower alkyl substituted by oxo or halogen;

R"? is selected from the group consisting of

H; lower alkyl; and lower alkyl substituted by NR’R® or OR";

R"’ and R" are each independently selected from the group consisting of o 1; lower alkyl; So lower alkyl substituted by CO,R'?, OR'?, NR’R®, C(O)NR’R?, SO,R!®, NSO.R'?, heteroaryl, heterocycle, or heterocycle substituted by oxo; cycloalkyl; cycloalkyl substituted by CO,R'?, OR'?, NR’RS, C(O)NR’R® or SO,R'%; aryl; aryl substituted by NR’R®, OR, CO,R'?, CONRR®, SO,R"’, halogen, lower alkyl, and lower alkyl substituted by halogen, OR'2, oxo, CO.R'?, C(O)NR’R® or NR°R®

SO.RY;

CO-R'%

COR'% and :

OR?

R10. | _o or alternatively, NRUR can form a ring having 3 to 7 ring atoms, said ring optionally ] including one or more additional N or O ring atoms and optionally being substituted by

OH, oxo, NR’R®, lower alkyl and lower alkyl substituted by. OR"

R'is selected from the group consisting of : aryl;

PCT/EP2004/000971 aryl substituted by the group halogen, CO,R'?, SO,R'%, COR'?, lower alkyl and lower alkyl substituted by halogen, OR'?, oxo, CO,R'?, C(O)NR’R® or NR’R; heteroaryl; heteroaryl substituted by the group halogen, CO,R'?, SOR", COR, lower alkyl and lower alkyl substituted by halogen, OR'2, oxo, CO;R'?, C(O)NR’R® or NR°R®;

NRR%; lower alkyl; lower alkyl substituted by halogen, OR", oxo, COR", C(O)NR°R® or NR°R%; heterocycle, and heterocycle substituted by the group CO,R", COR", SO,R', COR" lower alkyl,

C(O)NR’R®or NR’R’;

R'® and RY are each independently selected from the group consisting of

H; and lower alkyl; or, alternatively, the group —-NR'RY can form a ring having 3 to 7 ring atoms, said ring optionally including one or more additional N or O ring atoms and optionally being substituted by lower alkyl, OH, oxo and NH; and n 1s0,lor2; or the pharmaceutically acceptable salts or esters thereof.

These compounds inhibit cydin-dependent kinases, most particularly cyclin- dependent kinase 4 (Cdk4). Thus, compounds of formula I and their pharmaceutically acceptable salts and esters have antiproliferative activity and are useful, inter alia, in the treatment or control of cancer, in particular solid tumors. This invention also relates to pharmaceutical compositions containing such compounds and to methods of treating or controlling cancer, most particularly the treatment or control of breast, lung, colon and prostate tumors. Finally, this invention is also directed to novel intermediate compounds useful in the preparation of the novel diaminopyrimidines herein disclosed.

Uncontrolled cell proliferation is the hallmark of cancer. Cancerous tumor cells typically have some form of damage to the genes that directly or indirectly regulate the cell-division cycle.

AMENDED SHEET

) The progression of cells through the various phases of the cell cycle is regulated bya series of multienzyme complexes consisting of a regulatory protein, a cyclin, and a kinase.

These kinases are called cyclin-dependent kinases (Cdks). The Cdks are expressed ’ throughout the cell cycle, while the levels of the cyclins vary depending on the stage of the cell cycle. ) :

The four primary phases of cell cycle control are generally describes as Gy, S, Go, and M. Some essential enzymes for cell cycle control appear to be cyclin D/Cdk4, cyclin

D/Cdks, cyclin E/Cdk2, cyclin A/Cdk2, and cyclin B/Cdk1 (also known as Cdc2/cyclin

B). Cyclin D/Cdk4, cyclin D/Cdk6, and cyclin E/Cdk?2 control passage through the G;- 10 ., phase and the G;- to S-phase transition by phosphorylation of the retinoblastoma phosphoprotein, pRb. Cyclin A/Cdk2 regulates passage through the S-phase, and cyclin

B/Cdk1 controls the G, checkpoint and regulates entry into M (mitosis) phase.

The cell cycle progression is regulated by Cdk1 (cdc2) and Cdk2 beyond early G, when cells are committed to cytokinesis. Therefore, drug inhibition of these Cdks is ~ 15 likely not only to arrest cell proliferation, but also to trigger apoptotic cell death. Once the cells pass the G, restriction point and are committed to$ phase, they become independent of growth factor stimulation for continued cell cycle progression.

Following completion of DNA replication, cells enter the G; phase of the cell cycle in preparation for M phase and cytokinesis. Cdk1 has been shown to regulate passage of cells through these later phases of the cell cycle in association with both cyclins A and B.

Complete activation of Cdk1 requires both cyclin binding and specific phosphorylation (Morgan, D. O., De Bondt, H. L., Curr. Opin. Cell. Biol. 1994, 6, 239-246). Once activated, Cdk1/cyclin complexes prepare the cell for division during M phase.

The transition from G; phase into S phase as stated above is regulated by the complex of Cdk4 with cyclin D and Cdk2.with cyclin E. These complexes phosphorylate the tumor suppressor protein Retinoblastoma (pRb), releasing the transcription factor

E2F and allowing the expression of genes required in S phase (Nevins, J. R. Science 1992, 258, 424-429; Lavia, P. BioEssays 1999, 21, 221-230). Blocking the activity of the

Cdkd/cyclin D and Cdk2/cyclin E complexes arrests the cell cycle in G; phase. For

Co 30 example, the proteins of the INK4 family, including p16™%* which block the kinase activity of the Cdk4/cyclin D complex, cause arrest in G; (Sherr, C.J]. Science 1996, 274, 1672-1677). The specific block has been reviewed (Vidal, A. Gene 2000, 247, 1-15).

Recent experiments show that the complex of Cdkd4 with cyclin D3 also plays a role in cell cycle progression through G; phase. Inhibition of this complex, either by pl6 or

- using a‘ dominant negative Cdkd, results in arrest in G, phase in cells that do not express

PRb (Gabrielli B. G. et al. J. Biol, Chem. 1999, 274, 13961-13969). . . Numerous defects in the pRb pathway have been shown to be involved in various cancers. For example, overexpression of Cdk4 has been observed in cases of hereditary . 5 melanoma (Webster, K. R. Exp. Opin. Invest. Drugs 1998, 7, 865-887); cyclin D is overexpressed in many human cancers (Sherr, C. J. Science 1996, 274, 1672-1677); p16 is mutated or deleted in many tumors (Webster, K. R. Exp. Opin. Invest. Drugs 1998, 7, 865- 887); and pRb function is lost through mutation or deletion in many human cancers (Weinberg, R. A. Cell 1995, 81, 323-330). Defects in this pathway have also been shown + to have an effect on prognosis. For example, loss of p16 is correlated with poor prognosis in non-small-cell lung carcinoma (NSCLC) and malignant melanoma (Tsihlias, J. et al.

Annu. Rev. Med. 1999, 50, 401-423). Abnormalities of cyclin D1'and/or pRb at the gene and/or expression level were present in more than 90% of a series of non-small cell lung cancer specimens, indicating that cyclin D1 and/or pRb represent an important step in lung tumorigenesis (Marchetti, A. et al. Int. J. Cancer 1998, 75, 573-582). In 49 out of 50 pancreatic carcinomas (98%), the pRb/p16 pathway was abrogated exclusively through inactivation of the p16 gene and cyclin D connected (Schutte, M. et al. Cancer Res. 1998, 57,3126-3134). For a review on the relation between expression of pRb and the cyclin/cyclin dependent kinases in a number of tissues see Teicher, B.A.. Cancer

Chemother. Pharmacol. 2000, 46, 293-304.

Because of the involvement of the Cdk4/cyclin D/pRb pathway in human cancer through its role in regulating progression of the cell cycle from G; to S phase, and the potential therapeutic benefit from modulating this pathway, there has been considerable interest in agents that inhibit or promote elements of this pathway. For example, effects on cancer cells have been shown using antibodies, antisense oligonucleotides and overexpression or addition of proteins involved in the pathway. See, e.g., Lukas, J. et al.

Nature 1995, 79, 573-582; Nevins, J. R. Science 1992, 258, 424-429; Lim, I. K. et al.

Molecular Carcinogenesis 1998, 23, 25-35; Tam, S. W. et al. Oncogene 1994, £, 2663-2674;

Driscoll, B. et al. Am. J. Physiol. 1997, 273 (Lung Cell. Mol. Physiol. ), 1.941-1.949; and

Sang, J. et al. Chin. Sci. Bull. 1999, 44, 541-544).

The role of cdks in the regulation of cellular proliferation is thus well established.

For example, as shown above, there is an extensive body of literature validating the use of compounds inhibiting targets in the Cdk4 , Cdk2 and Cdk1 pathways as anti-proliferative : therapeutic agents. Inhibitors of cellular proliferation thus act as reversible cytostatic ; agents that are useful in the treatment of disease processes which feature abnormal cellular growth, such as cancers and other cell proliferative disorders including, for example inflammation (e.g. benign prostate hyperplasia, familial adenomauosis, oo

: PCT/EP2004/000971 polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, inflammatory bowel disease, transplantation rejections infections), viral infections (including, but not limited to herpervirus, poxvirus, Epstein-Barr virus), autoimmune disease (e.g. lupus, rheumatoid arthritis, psoriasis, inflammatory bowel disease), neurodegenerative disorders (including but not limited to Alzheimer’s disease), and neurodegenerative diseases (e.g. Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy, and cerebral degeneration).

Several distinct classes of small molecules have been identified as inhibitors of

Cdks: olomoucine and other purine analogs, flavopiridol, staurosporine, UCN-01 and other indolocarbazoles, 9-hydroxyellipticine, indirubin, paullones, diaryl ureas, quinazolines, indopyrazoles, [2,3-d] pyridopyrimidines, fascaplysin, aminothiazoles, diaminothiazoles, pteridinones, and pyrazoles or example (Carlson et. al., Cancer Res. 1996, 56, 2973-2978: De Azevedo et al., Eur. J. Biochem., 1997, 243, 518-526; Bridges, A.].,

Exp. Opin. Ther. Patents. 1995, 5, 1245-1257; Reinhold et al., J. Biol. Chem. 1998, 278, 3803-3807; Kakeya, H. et. al., Cancer Res.. 1998, 38, 704-710; Harper, J.W., Cancer

Surveys 1997, 29, 91-107; Harrington, E.A, etal., Proc Natl. Acad. Sci. USA 1998, 95, 11945-11950; Meijer, L., et al., Eur. J. Biochem. 2000, 267, 1-13; Garrett, M.D. et. al,

Current Opin. Genetics Develop. 1999, 9, 104-111; Mgbonyebi, O. P. et al., Cancer Res.. 1999, 59, 1903-1910; Hoessel et al., Nature Cell Biology. 1999, 1, 60-67; Zaherevitz et al.,

Cancer Res., 1999, 59, 2566-2569; Honma, T., et al, 271% National ACS Meeting. 2001:

Medi 136; Sielecki, T.M., et al., Bioorg. Med. Chem. Lett. 2001, 11, 1157-1160; Nugiel, D.

A. etal, J. Med. Chem., 2001, 44, 1334-1336; Fry, D. W. etal, J. Biol. Chem. 2001, 276, 16617-15523; Soni, R., et al., Biochem. Biophys. Res. Commun. 2000, 275, 877; Ryu, C-K. et al., Bioorg. Med. Chem. Lett., 2000, 10, 461; Jeong, H-W.,, etal, Bioorg. Med. Chem.

Lett. 2000, 10, 1819; Toogood et al., J. Med. Chen., 2000, 43, 4606-4616; Chong, W.,

Fischer, Curr. Opin. in Drug Discov. and Develop., 2001, 4, 623-634, WO0009921845,

Toogeod. P., WO0119825, Toogood P., WO0138315, Reich S.H., WO0179198, Webster,

K. US 6,262,096.

The class of diaminopyrimidines is represented by compounds of formula

AN

9

Sw . af stated to inhibit Cdk4 and FAK3. See WO0012485 (Astra Zeneca).

AMENDED SHEET

-10- SE

WO9118887 (Smith Kline Beecham) relates to diaminopyrimidines of formula . AR! - 4 ’

Be

RN ONRR® that are stated to inhibit gastric secretion.

WO0039101 (Astra Zeneca) relates to pyrimidine compounds of formula 1

QR

NT R

A ~

Q—N N

H stated to act as anti-cancer agents. :

WO0164653 (Astra Zeneca) relates to pyrimidine compounds of the formula 2

N~ SN . rR described to act as Cdk inhibitors and FAK inhibitors.

WQO0164654 (Astra Zeneca) relates to pyrimidine compounds of formula por

HM :

Ny . R' described to act as Cdk inhibitors and FAK inhibitors. ’

Additionally, WO0164656 (Astra Zeneca) relates to pyrimidine compounds of formula. : Co Co

. q y Sn : | LA C

R' : also described as Cdk inhibitors and FAK inhibitors.

For reviews of compounds inhibiting the Cdk4/cyclin D pathway see: Harris, W. and Wilkinson, S., Emerging Drugs.. 2000, 5, 287-297; Dumas, J., Exp. Opin. Ther. Patents. 5 . 2001, 11, 405-429; Sielecki T., et. al., J. Med. Chem.. 2000, 43, 1-18.

The present invention relates to novel diaminopyrimidines of the formula

NH, O

NT R2

A i) N 1

R I wherein

R' is selected from the group consisting of heterocycle and lower alkyl-heterocycle, wherein the heterocycle moiety in both instances optionally may be substituted by up to four substituents independently selected from

H, - lower alkyl, : lower alkyl substituted by oxo, OR", COR", NR’RS, S(0)aR or

C(O)NR’RS,

CO,R’,

COR", : COR",

C(O)NRVRY,

S(O)aR", 0X0, ~ ORY or

NR’RS;

-12- | SE - aryl; aryl substituted by -S(0)4-R",

NR’RS, carbonyl, carbonyl substituted by lower alkyl, OR" or NR’RS, lower alkyl, lower alkyl substituted by OR'® or NR°RS, 10. OR? or .

Halogen; cycloalkyl; cycloalkyl substituted by OR’, NR’R® or S(O), R** lower alkyl; and lower alkyl substituted by

NR’R®

NR"SO,R",

COR", :

S(O)R", heterocycle, heterocycle substituted by : lower alkyl,

COR"? or

SOR, h heteroaryl, heteroaryl substituted by lower alkyl, _ CORY, or

SOR", aryl, and aryl substituted by lower alkyl, ~~ halogen,

-13- SE. } © NR°RS,

CORY, or

CORY}

R® is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocycle, wherein each may be substituted by up - to four substituents independently selected from the group consisting of lower alkyl, lower alkyl substituted by halogen or OR, v halogen,

OR",

NO,

CN,

NR°RS, $(0)x-R’ and

SE SO,-NR"R";

R’® and R® are each independently selected from the group consisting of

H; lower alkyl; : lower alkyl substituted by oxo, CO,R'2, ORY, NRR", C(O)NR"R™, SO,R',

NSO,R', heteroaryl, heterocycle, or heterocycle substituted by oxo; cycloalkyl; cycloalkyl substituted by CO,R'%, OR'%, NR" R'*, C(O)NR"R" or SO,R'® aryl; aryl substitut=d by NRPRY, ORY, CO,R'2, C(O)NRPR , SO,RY, halogen, lower alkyl, or lower alkyl substituted by halogen, OR'?, oxo, CO,R", C(O)NRPR" or ’ NRIPRY : . : SO.R™;

CORY;

COR'% and

14-0 oo ) OR"? wo | o or alternatively, NR R® can form a ring having 3 to 7 ring atoms, said ring optionally : including one or more additional N or O ring atoms or the group SO, and optionally being substituted by OH, oxo, NR"’R*, lower alkyl and lower alkyl substituted by OR'%;

R’ is selected from the group consisting of " H; : lower alkyl; lower alkyl substituted by OR'?, COR", NR°R, or C(O)NR’R® halogen; 0X0; aryl; aryl substituted by up to three substituents independently selected from lower alkyl, halogen and NR°R® cycloalkyl; cycloalkyl substituted by OH, oxo, or NH.

SO;R'* and | 3

COR";

R® is selected from the group consisting of

H; oo 20 lower alkyl; lower alkyl substituted by NR’R® heterocycle; and ~ heterocycle substituted by lower alkyl, CO.R'? or SO:R' > so ) R’ isselected from the group consisting of

H; and lower alkyl;

R'is selected from the group consisting of lower alkyl; aryl; and aryl substituted by halogen or NR’R%

R'" is selected from the group consisting of :

H; lower alkyl; and lower alkyl substituted by oxo or halogen; * R'? is selected from the group consisting of

H; lower alkyl; and lower alkyl substituted by NR°R® or OR";

R" and R" are each independently selected from the group consisting of

Hj lower alkyl; lower alkyl substituted by CO.R'%, OR'?, NR’R®, C(O)NR’R®, SO,R"’, NSO,R"?, heteroaryl, heterocycle, or heterocycle substituted by oxo; cycloalkyl; cycloalkyl substituted by CO,R'?, OR'?>, NRR®, C(O)NR’R’ or SO.R'; aryl; aryl substituted by NR’R®, OR'?, CO,R"2, CONR’R’, SO,R", halogen, lower alkyl, and lower alkyl substituted by halogen, OR? 0x0, CO,RY, C(O)NR’R® or NR°R®

SOR;

COR

. CORY; and : OR12 wo lo

: : PCT/EP2004/000971 or alternatively, -NR'’R' can form a ring having 3 to 7 ring atoms, said ring optionally including one or more additional N or O ring atoms and optionally being substituted by

OH, oxo, NRR®, lower alkyl and lower alkyl substituted by ORY;

R!® is selected from the group consisting of aryl; aryl substituted by the group halogen, COR", SOR, COR", lower alkyl and lower alkyl substituted by halogen, ORY, oxo, COR'2, C(O)NR°R® or NRR’; heteroaryl; heteroaryl substituted by the group halogen, CO,RY, SO,R', CORY, lower alkyl and lower alkyl substituted by halogen, OR'?, oxo, CO,R'2, C(O)NR®R® or NR°R’;

NR°RS; lower alkyl;

Jower alkyl substituted by halogen, OR", oxo, CORY, C(O)NR’R® or NR’R’; heterocycle, and heterocycle substituted by the group CO,R", CORY, SO.RY, COR? lower alkyl,

C(O)NR’R®or NR’R%;

R!S and RY are each independently selected from the group consisting of

H; and lower alkyl; or, alternatively, the group _NR¥RY can form a ring having 3 to 7 ring atoms, said ring optionally including one or more additional N or O ring atoms and optionally being substituted by lower alkyl, OH, oxo and NHz: and n is0,1 012; or the pharmaceutically acceptable salts or esters thereof.

These compounds inhibit cyclin-dependent kinases, most particularly Cdk4. These compounds and their pharmaceutically acceptable salts and esters have antiproliferative activity and are useful in the treatment or control of cancer, in particular solid tumors.

AMENDED SHEET

-17- oo

The present invention also relates to pharmaceutical compositions comprising one or more compounds of the invention, or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier or excipient.

The present invention further relates to a method for treating or controlling cancer, more particularly the treatment or control of a solid tumor, most particularly to the treatment or control of breast, lung and colon and prostate tumors by administering to a patient in need of such therapy a therapeutically effective amount of a compound of formula I, or a pharmaceutically salt or ester thereof. . Finally, this invention also relates to a process for the preparation of compounds of formula I and to novel intermediate compounds useful in the preparation of a compound of formula I. RT

As used herein, the following terms shall have the following definitions. : "Aryl" means a monovalent, monocyclic or bicyclic, aromatic carbocyclic hydrocarbon radical, preferably a 6-10 membered aromatic aromatic ring system.

Preferred aryl groups include, but are not limited to, phenyl, naphthyl, tolyl and xylyl. "Carbonyl" means the radical C=0. ~ "Cycloalkyl" means a non-aromatic, partially or completely saturated monovalent cyclic hydrocarbon radical containing 3 to 8 atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. "Effective amount" means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. “Halogen” means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine. “Hetero atom” means an atom selected from N, O and S. "Heteroaryl" means an aromatic heterocyclic ring system containing up to two rings. Preferred heteroaryl groups include, but are not limited to, thienyl, furyl, indolyl, ) pyrrolyl, pyridinyl, pyridine, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazolyl, benzofuranyl and tetrazolyl. EE "Heterocycle" or "heterocyclyl" means a saturated or partially unsaturated, non- aromatic cyclic radical of 3 to 8 ring atoms in which from 1to 3 ring atoms are hetero "atoms selected from nitrogen, oxygen, S(O), (where n is an integer from 0 to 2), ora

-18- oo ) combination thereof, the remaining ring atoms being C. Examples of preferred heterocycles are piperidine, piperazine, pyrrolidine, morpholine, indoline, tetrahydropyranyl, thiomorpholino, pentamethylene sulfide, and pentamethylene sulfone. “ICs” refers to the concentration of a particular compound according to the invention required to inhibit 50% of a specific measured activity. ICsp can be measured, inter alia, as is described in Example390A4, infra. “K,” refers to a measure of the thermodynamic binding of the ligand/inhibitor (that

Lisa compound according to the invention) to the target protein. K; can be measured, inter alia, as is described in Example 390B, infra. “Lower alkyl” alone or in conjunction with another term, e.g. lower alkyl- heterocycle, denotes a straight-chain or branched saturated aliphatic hydrocarbon having 1 to 6, preferably 1 to 4, carbon atoms. Typical lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 2-butyl, pentyl, hexyl and the like. "Oxo" means =O. “Pharmaceutically acceptable ester” refers to a conventionally esterified compound of formula I having a carboxyl group, which esters retain the biological effectiveness and properties of the compounds of formula I and are cleaved in vivo (in the organism) to the corresponding active carboxylic acid. Examples of ester groups which are cleaved (in this case hydrolyzed) in vivo to the corresponding carboxylic acids (R¥C(=0)OH) are lower alkyl esters which may be substituted with NR*'R*? where R* and R*? are lower alkyl, or where NR*'R*? taken together form a monocyclic aliphatic heterocycle, such as pyrrolidine, piperidine, morpholine, N-methylpiperazine, etc.; acyloxyalkyl esters of the formula R¥C(=0)OCHR*0C(=0)R* where R® is hydrogen or methyl, and R* is lower alkyl or cycloalkyl; carbonate esters of the formula R¥*C(=0)OCHR* OC(=0)OR* where R® is hydrogen or methyl, and R® is lower alkyl or cycloalkyl; or ' aminocarbonylmethyl esters of the formula R®C(=0)OCH,C(=0)NR*'R* vihere RY and R* are hydrogen or lower alkyl, or where NR*R* taken together form a monocyclic aliphatic heterocycle, such as pyrrolidine, piperidine, morpholine, N-methylpiperazine, etc. a

Examples of lower alkyl esters are the methyl, ethyl, and n-propyl esters, and the : like. Examples of lower alkyl esters substituted with NR*R* are the diethylaminoethyl, 2- (4-morpholinyl)ethyl, 2-(4-methylpiperazin-1-yl)ethyl esters, and the like. Examples of acyloxyalkyl esters are the pivaloxymethyl, 1-acetoxyethyl, and acetoxymethyl esters. N

Examples of carbonate esters are the 1-(ethoxycarbonyloxy)ethyl and 1-

(cyclohexyloxycarbonyloxy) ethyl esters. Examples of aminocarbonylmethyl esters are the

N,N-dimethylcarbamoylmethyl and carbamoylmethyl esters.

Further information concerning examples of and the use of esters for the delivery of pharmaceutical compounds is available in Design of Prodrugs. Bundgaard Hed. ’ 5 (Elsevier, 1985). See also, H. Ansel et. al., Pharmaceutical Dosage Forms and Drug

Delivery Systems (6th Ed. 1995) at pp. 108-109; Krogsgaard-Larsen, et. al., Textbook of

Drug Design and Development (2d Ed. 1996) at pp. 152-191. “Pharmaceutically acceptable salt” refers to conventional acid-addition salts or , base-addition salts that retain the biological effectiveness and properties of the compounds of formula I and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluene sulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Sample base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide. The chemical modification of a pharmaceutical compound (i.e. drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g,

H. Ansel et. al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 196 and 1456-1457. “Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered: “Substituted,” as in substituted alkyl, means that the substitution can occur at one or more positions and, unless otherwise indicated, that the substituents at each substitution site are independently selected from the specified options. “Therapeutically effective amount” means an amount of at least one compound of

Formula I, or a pharmaceutically acceptable salt or ester thereof, that significantly : inhibits proliferation and/or prevents differentiation of a human tumor cell, including human tumor cell lines.

: In one embodiment, the present invention relates to compounds of formula I : NH, O . NT R2

PY = i) N : : : R 1, or the pharmaceutically acceptable salts or esters thereof, wherein R' and R® are as , defined above.

In a preferred embodiment of the compounds of formula I, R? is phenyl, preferably phenyl substituted by halogen, most preferably F, or OR"? wherein R'? is lower alkyl. Ina most preferred embodiment, R? is phenyl substituted by one or two F molecules and one

OR"? group wherein R'is lower alkyl, preferably methyl.

In another preferred embodiment of the compounds of formula I, R? is as defined above and R' is selected from the group (3 A ) SE No

R3 - OX Rs (a), (b), (c)

Ré

R4 4 .

REC i \ ZN

Re R® RS OR". (d), (e)s (0,

-21- SE. : oe

R# RY i $(0),

NJ | Lis

RS Re Re (2) (h) and - (i), wherein ‘Rs selected from the group consisting of

H, or lower alkyl, lower alkyl substituted by oxo, OR", CO,R'?, NR’R?, SO,R** or C(O)NRRS,

COR,

CORY,

C(O)NR’R’, and

SOR";

R* is selected from the group consisting of

H, y

OR! : Co lower alkyl,

NRR’,

NO, 0X0

CN, and - halogen;

RY is selected from the group consisting of

H,

OR! 1 lower alkyl,

NR°R’,

NO.,

CN, and halogen;

R’and R® are each independently selected from the group consisting of

: PCT/EP2004/000971

H, lower alkyl, lower alkyl substituted by oxo, CO;R'2, OR, NRPR™, C(O)NR"R™, SO.RY,

NSO;R'3, heteroaryl, heterocycle, or heterocycle substituted by oxo, cycloalkyl, cycloalkyl substituted by CO;R'2, OR™2, NR"R", C(O)NRR' or SOR”, aryl, aryl substituted by NR°R*, OR", CO,R", C(O)NR"R', SOR", halogen, lower alkyl, and lower alkyl substituted by halogen, OR'?, oxo, CORY, C(O)NRPR" and

NRPR'™;

SOR",

CO:RY,

COR", and

OR™2

R11 OL | = or alternatively, -NR°R® can form a ring having 3 to 7 atoms, said ring optionally including one or more additional N or O atoms and optionally being substituted by OH, oxo, NRPR", lower alkyl and lower alkyl substituted by OR'%

R is selected from the group consisting of

H, lower alkyl, lower alkyl substituted by OR", CO;R'?, NR’R’, or CONR’R, halogen, oxo, aryl, aryl substituted by up to three substituents independently selected from lower alkyl, halogen, and NR°R’, cycloalkyl, cycloalkyl substituted by OH, oxo, or NHo,

SOR", and

COR";

R® is selected from the group consisting of

H, lower alkyl,

Jower alkyl substituted by NR’R®,

AMENDED SHEET

-23- a - heterocycle, and heterocycle substituted by lower alkyl, CO;R™? or SOR;

R'® is selected from the group consisting of lower alkyl, aryl, and aryl substituted by halogen or NR°R;

R'" is selected from the group consisting of

H, lower alkyl, and lower alkyl substituted by oxo and halogen;

R'is selected from the group consisting of

H, lower alkyl, and lower alkyl substituted by halogen, oxo, NR°R® or OR"};

R” and R" are independently selected from the group consisting of

H, a lower alkyl, lower alkyl substituted by CO,R'2, ORY, NR°RS, C(O)NR'RS, SO.R'®, NSO,R'2, heteroaryl, heterocycle, or heterocycle substituted by oxo, cycloalkyl, cycloalkyl substituted by CO,R'?, OR", NR’R®, C(O)NRR® or SO,R", aryl, aryl substituted by NR°R®, OR'%, CO;R'?, C(O)NR’R?, SO,R*, halogen, lower alkyl, and lower alkyl substituted by halogen, OR", 0x0, CO,R'%, C(O)NR’R® and NR°RS;

SOR",

CO.R",

CORY, and

OR12 i

RO ~ AO : or alternatively, -NR'’R" can form a ring having 3 to 7 ring atoms, said ring optionally including one or mors additional N or O ring atoms and optionally being substituted by

OH, oxo, NR’R®, lower alkyl and lower alkyl substituted by OR'%;

R"” is selected from the group consisting of aryl, Ce aryl substituted by the group halogen, COR"? SOR’, COR", lower alkyl and lower alkyl substituted by halogen, OR'?, 0x0, CO,R'%, C(O)NR’R® or NR°RS, : heteroaryl, : . Lo SE heteroaryl substituted by the group halogen, COR", SO.R'%; COR? lower alkyl and lower alkyl substituted by halogen; ORY, 0XO0, CORY, C(O)NR°R® or NR? RS,

- | 224 - Co . NR°R’, lower alkyl, lower alkyl substituted by the group halogen, OR'?, oxo, CO,R'2, C(O)NR°R® or : NR’RS, heterocycle, and : heterocycle substituted by the group CO,R*?, COR? SO;R", lower alkyl

C(O)NR’R® or NR°RS;

X isselected from the group consisting of

S, SO, SO,, and O; and n is0,1lor2; or the pharmaceutically acceptable salts or esters thereof, Co

In another preferred embodiment, the invention relates to compounds of formula : NH, O

R21

N 7

R18 20 bg :

HN R10 @), 18 : wherein R® and R* are as defined above and R'®, R”, R®* and R* are each independently selected from lower alkyl, halogen and OR. Preferably, R? is selected from the group

CO,R’, COR? and SO,RY.

Most preferably R? is SO,R'* and RY is lower alkyl or NR°R®, Preferred R’ groups include H, OR" and lower alkyl. Preferred R’ and R® groups are those wherein the group -NR’R® forms a ring having 3 to 7 ring atoms, said ring optionally including one or more additional N or O ring atoms and optionally being substituted by OH, oxo and NH, lower alkyl or lower alkyl substituted by OR'2.

Examples of compounds of formula I(a) include: oe Co - . 4-[4-amino-5-( 2-methoxy-benzoyl)-pyrimidin-2-ylamino -piperidine- 1 carboxylic acid - ethyl ester (Example 9), Co oo :

w WO 2004/069139 PCT/EP2004/000971 -25- S. 4-[4-amino-5-(2,6-difluoro-benzoyl)-pyrimidin-2-ylamino)-piperidine- 1-carboxylic acid ethyl ester (Example 16), 4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine- 1- carboxylic acid ethyl ester (Example 51), 1-[4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]- piperidin-1-yl] -ethanone

Co (Example 20), 1-[4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino)-piperidin-1-yl]-propan-1- one (Example 21), 1-[4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-butan-1- one (Example 22), oT 1-[4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl}-3-methyl- butan-1-one ( Example 23), : 1-[4-[4-Amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl] -3- diethylamino-propan-1-one (Example 24), 4-[4-amino-5-(2-methyl-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid ethyl ester (Example 35), 4- (4-Amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino] -piperidine-1-carboxylic acid methyl ester (Example 17), 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid propyl ester (Example 18), 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid iso-butyl ester ( Example 19), 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carbozylic acid methylamide (Example 25), 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid ethylamide (Example 26), ) 4- [4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino} -piperidine-1 -carboxylic acid propylamide (Example 27), -_ PERI Co

-26- C : [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy- phenyl)-methanone (Example 28), : . [4-amino-2-(1-ethanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]- (2-methoxy- phenyl)-methanone (Example 29),

[4-amino-2-[1-(propane-1-sulfonyl)-piperidin-4-ylamino)-pyrimidin-5-yl]-(2- methoxy-phenyl)-methanone (Example 30), 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl) -pyrimidin-2-ylamino]-piperidin-1-yl]- ethanone (Example 62), 4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1- :

carboxylic acid methyl ester (Example 60) 4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1- carboxylic acid propyl ester (Example 61), : 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]- propan-1l-one (Example 63),

1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]- butan-1-one (Example 64), a 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino] -piperidine-1-carboxylic acid dimethylamide (Example 57), [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-

methoxy-phenyl)-methanone ( Example 65), [4-amino-2-(1-ethanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl}-(5-fluoro-2- methozy-phenyl)-methanone (Example 66),

* [4-amino-2-[ 1-(propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-y1]-(5-flucro-2- methoxy-phenyl)-methanone (Ezample 67), [4-amino-2-( 1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(2-fluoro- phenyl)-methanone (Example 41), [4-amino-2-( I-ethanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(2-fluoro-phenyl)- methanone (Example 42), 7 CL : Co Le ;

27. S ) 4-[4-amino-5-(2-fluoro-benzoyl)-pyrimidin-2-ylamino}-piperidine-1-carboxylic acid ethyl ester (Example 40), [4-amino-2-(1 -trifluoromethanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(5- fluoro-2-methoxy-phenyl)-methanone (Example 68), 4-[4-amino-5-( 5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino] -piperidine-1- sulfonic acid dimethylamide (Example 160), 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]- 2-dimethylamino-ethanone (Example 81), 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl}- 2-diethylamino-ethanone (Example 82), oT 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]- 2-morpholin-4-yl-ethanone (Example 83), : 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]- 3-dimethylamino-propan-1-one (Example 84), 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl}- 3-diethylamino-propan-1-one (Example 85), 1-[4-[4-amino-5-( 5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino] -piperidin-1-yl]- 3-piperidin-1-yl-propan-1-one (Example 86), 1-[4~[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl}- 3-morpholin-4-yl-propan-1-one (Example 87), [4-amino-2-[1-(3,5-dimethyl-isoxazole-4-sulfonyl)-piperidin-4-ylamino}-pyrimidin-5- y1]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 161), [4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-v1]- acetic acid methyl ester (Example 159), 1-{4- [4-amino-5-(2,6-difluoro-3-methoxy-benzoyl)-pyrimidin-2-ylamino) -piperidin-1- yl]-ethanone (Example 90), ) [4-amino-2-( 1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-y1] -(2,6-difluoro-3- methoxy-phenyl)-methanone (Example 91), EE . RE oT

S28. oo ; 4-[4-amino-5-(2,6-difluoro-3-methoxy-benzoyl)-pyrimidin-2-ylamino] -piperidine-1- carboxylic-acid methyl ester (Example 94), : 1-[4-[4-amino-5-(2-ethoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl} -ethanone (Example 97), ‘

[4-amino-2-[1-(thiophene-3-sulfonyl)-piperidin-4-ylamino] -pyrimidin-5-yl] -(5-fluoro- 2-methoxy-phenyl)-methanone (Example 153), [4-amino-2-[1-(benzo[b]thiophene-3-sulfonyl)-piperidin-4-ylamino}-pyrimidin-5-yl]- (5-fluoro-2-methoxy-phenyl)-methanone ( Example 154), [4-amino-2-{1-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)-piperidin-4-ylamino}-

pyrimidin-5-yl}-(5-fluoro-2-methoxy-phenyl)-methanone (Example 155), 3-{4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1- sulfonyl]-thiophene-2-carboxylic acid methyl ester (Example 156), (4-amino-2-[1-(2,5-dimethyl-thiophene- 3-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5- y1]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 152),

4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino}-piperidine-1- carboxylic acid cyclohexylamide (Example 145), ” 1-[4-[4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino] -piperidin-1- yl]-ethanone (Example 104), (4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-

methoxy-phenyl)-methanone (Example 105), [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone (Example 11),

[4-amino-2-{piperidin-4-ylamino)-pyrimidin-5-y1] -(5-fluoro-2-methoxy-phenyl)- methanone (Example 59), oo 25 [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)- methanone (Example 107), i 1-[4-[4-amino-5-(2,3 ,4-trifluoro-6-methoxy-benzoyl) -pyrimidin-2-ylamino] -piperidin- 1-yl]-ethanone (Example 204), Sl nL Bh Co N Lo CL

-29- J - [4-amino-2-( 1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(3,4,5-trifluoro- 2-methoxy-phenyl)-methanone (Example 206), : [4-amino-2-(1 -methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -( 2,3 4-trifluoro- 6-methoxy-phenyl)-methanone (Example 207), [4-amino-2-[1- (2-methanesulfonyl-ethyl) -piperidin-4-ylamino] -pyrimidin-5-y1] -(5- fluoro-2-methoxy-phenyl)-methanone (Example 209), 1-[4-[4-amino-5-(5-fluoro-2-methyl-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-y1]- ethanone (Example 211), : (4-amino-2-(1 -methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(5-fluoro-2- : methyl-phenyl)-methanone (Example 213), oT [4-amino-2-(1 -methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(5-fluoro-2- trifluoromethyl-phenyl)-methanone (Example 214), [4-amino-2-( 1-methanesulfonyl-piperidin-4-ylamino) -pyrimidin-5-yl]-(5-fluoro-2- 1sopropoxy-phenyl)-methanone (Example 215), [4-amino-2-( 1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(2-ethoxy-5- fluoro-phenyl)-methanone (Example 216), [4-amino-2-( 1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(2-ethyl-5- fluoro-phenyl)-methanone (Example 217), [4-amino-2-(1 -methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(2-methoxy-4- trifluoromethyl-phenyl)-methanone ( Example 218), 4-[4-amino-5-(2-fluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1- carboxylic acid tert-butyl ester (Example 222), [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-fluoro-6-methozy-phenyl)- methanone (Example 223), [4-amino-2-(1 -methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-71] -(2-fluoro-6- methoxy-phenyl)-methanone (Example 224), 1-[4-[4-amino-5- (2-fluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino] -piperidin- 1-yl]- 2,2,2-trifluoro-ethanone (Example 225), — PEER REE

-30- SE ) [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino] -pyrimidin-5-yl]- (2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226), (4-amino-2-[1-[3-(2-hydroxy-1-methyl-ethylamino)-propane-1-sulfonyl] _piperidin-4- ylamino]-pyrimidin®5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 227), (4-amino-2-[1-[3-(4-methyl-piperazin-1-yl)-propane-1-sulfonyl] piperidin-4-ylamino) -

: pyrimidin-5-y1)-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 228), (4-amino-2-[1-[3-((R)-1-hydroxymethyl-propylamino)-propane-1-sulfonyl]-piperidin- 4-ylamino|-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example

229), [4-amino-2-[1-(3-hydroxy-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]- (2,3-difluoro-6-methoxy-phenyl)-methanone (Example 230), [4-amino-2-[1-(3-pyrrolidin-1-yl-propane-1-sulfonyl)-piperidin-4-ylamino}-pyrimidin-

: 5-y1]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 231), [4-amino-2-[1-(3-morpholin-4-yl-propane-1-sulfonyl)-piperidin-4-ylamino]-

pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 232), [4-amino-2-(1-[3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propane-1-sulfonyl}-piperidin- 4-ylamino)-pyrimidin-5-yl] -(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 233), : [4-amino-2-(1-[3-[(2-methoxy-ethyl)-methyl-amino]-propane-1-sulfonyl]-piperidin-4-

ylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 234), (4-amino-2-[1-[3-(2-hydroxy-1,1-dimethyl-ethylamino)-propane- 1-sulfonyl] -piperidin- 4-ylamino]-pyrimidin-5-y1)-(2,3-difluoro-6-methozxy-phenyl)-methanone (Example 235),

(4-amino-2-[1-[3-(2-hydroxy-propylamino)-propane- 1-sulfonyl]-piperidin-4-ylamino]-

pyrimidin-5-y1)-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 236), (4-amino-2-[1-[3-((S)-2-hydroxy- 1-methyl-ethylamino)-propane-1-sulfonyl]-piperidin-

. 4-ylamino]-pyrimidin-5-y1)-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 237), Co I (4-amino-2-[1- (3-((R)-1-hydroxymethyl-2-methyl-propylamino)-propane- I-sulfonyl]-

piperidin-4-ylamino]-pyrimidin-5-y})-( 2,3-difluoro-6-methoxy-phenyl)-methanone (Example 238), oo | SE

-31- SE (4-amino-2-[1-[3~((R)-2-hydroxy-1-methyl-ethylamino)-propane-1-sulfonyl] - piperidin-4-ylamino]-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 239), (4-amino-2-[1-[3-({S)-1-hydroxymethyl-propylamino)-propane-1-sulfonyl}-piperidin-

' 5 4-ylamino)-pyrimidin-5-y1)-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 240), [4-amino-2-(1-[3-[3-hydroxy-1-(2-hydroxy-ethyl)-propylamino] -propane-1-sulfonyl]- piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone

(Example 241),

[4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5- fluoro-2-methoxy-phenyl)-methanone (Example 242), Co [4-amino-2-(1-[3-[(2-methoxy-ethyl)-methyl-amino]-propane-1-sulfonyl}-piperidin-4- ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 243), [4-amino-2-(1-[3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propane-1-sulfonyl] -piperidin-

4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 244), (4-amino-2-{1-[3-((S)-2-hydroxy-1-methyl-ethylamino)-propane- 1-sulfonyl} -piperidin- 4-ylamino]-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone (Example 245), (4-amino-2-[1-[3-((R)-1-hydroxymethyl-propylamino)-propane-1-sulfonyl] -piperidin- 4-ylamino]-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone (Example 246),

(4-amino-2-[1-[3-(2-hydroxy-propylamino)-propane-1-sulfonyl]-piperidin-4-ylamino]- pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone (Example 247), (4-amino-2-[1-[3-((R)-1-hydroxymethyl-2-methyl-propylamino)-propane-1-sulfonyl]- piperidin-4-ylamino]-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone (Example 248),

(4-amino-2-[1-[3-(2-methoxy-1-methyl-ethylamino)-propane-1-sulfonyl]-piperidin-4- ylamino]-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone (Example 249), (4-amino-2-[1-[3-(2-hydroxy-1,1-dimethyl-ethylamino)-propane-1-sulfonyl]-piperidin-

4-ylamino]-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone (Example 250), (4-amino-2-[1-[3-((R)-2-hydroxy-1-methyl-ethylamino)-propane- 1-sulforyl}- _ piperidin-4-ylamino]-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone (Example 251), Co

) -32- oo . (4-amino-2-[1-[3-((S)- 1-hydroxymethyl-propylamino)-propane- I-sulfonyl]-piperidin- 4-ylamino} -pyrimidin-5-yl)-( 5-fluoro-2-methoxy-phenyl)-methanone (Example 252), [4-amino-2-[1-( 4-hydroxy-butane-1 -sulfonyl) -piperidin-4-ylamino) -pyrimidin-5-yl] - (5-fluoro-2-methoxy-phenyl)-methanone (Example 253), ’ 5 [4-amino-2-(1-(4-chloro-butane-] -sulfonyl) -piperidin-4-ylamino] -pyrimidin-5-yl]-(5-

fluoro-2-methoxy-phenyl)-methanone (Example 255),

(4-amino-2-[1-[4-( 4-methyl-piperazin-1-yl)-butane-1 -sulfonyl)-piperidin-4-ylamino]- pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone (Example 256),

[4-amino-2-[1-(4-pyrrolidin-1 -yl-butane-1 -sulfonyl)-piperidin-4-ylamino]- pyrimidin-

5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 257), ~~

(4-amino-2-[1-[4-( 2-hydroxy-propylamino)-butane-1 -sulfonyl]-piperidin-4-ylamino]- pyrimidin-5-y)-(5-fluoro-2-methoxy-phenyl)-methanone (Example 258), [4-amino-2-( 1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-y1)-(2,3-difluoro- 5,6-dimethoxy-phenyl)-methanone (Example 261),

[4-amino-2-( 1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(2,3-difluoro-6- hydroxy-5-methoxy-phenyl)-methanone (Example 262), [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(2,3-difluoro- 5,6-dihydroxy-phenyl)-methanone (Example 263),

[4-amino-2-(1 -methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(2,3-difluoro-5-

hydroxy-6-methoxy-phenyl)-methanone (Example 271), (4-amino-2-[1-(3-chloro-propane- 1-sulfonyl)-piperidin-4-ylamino] -pyrimidin-5-yl]-(5- fluoro-2-methoxy-phenyl)-methanone (Example 272), [4-amino-2-[1-(3-pyrrolidin-1 -yl-propane-1 -sulfonyl)-piperidin-4-ylamino] -pyrimidin- 5-y1}-(5-fluoro-2-methoxy-phenyl)-methanone (Example 273), = 25 acetic acid 3-[4-4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino.- piperidine-1-sulfonyl]-propyl ester (Example 274), ; (4-amino-2-| 1-(3-hydroxy-propane-1 -sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-y1}- (5-fluoro-2-methoxy-phenyl)-methanone (Example 275), ~ B T Lo CL

33. | SE : [4-amino-2-[1-(3-morpholin-4-yl-propane-1 -sulfonyl)-piperidin-4-ylamino]-

Pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 276),

N-(3-[4-[4-amino-5-( 5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino] -piperidine- 1-sulfonyl]-propyl)-methanesulfonamide (Example 277), (4-amino-2-[1-[3-(4-methyl-piperazin-1-yl)-propane-1-sulfonyl] -piperidin-4-ylamino]- : pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone (Example 278), [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl}-(2,3-difluoro-6- _hydroxy-phenyl)-methanone (Example 279), [4-amino-2-( 1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-phenyl- : methanone (Example 283), oT 4-[4-amino-5-( 2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino}-piperidine-1- carbaldehyde (Example 284), : 4-[4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1- sulfonic acid amide (Example 285), 4-[4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1- sulfonic acid acetyl-amide (Example 286), ” rac-(4-amino-2-(3-hydroxy- 1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl} - (2,3-difluoro-6-methoxy-phenyl)-methanone (Example 306), rac-[4-amino-2-(3-hydroxy-1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl} - (2,3-difluoro-6-methoxy-phenyl)-methanone (Example 310), rac-(4-amino-2-(1-methanesulfonyl-3-methoxy-piperidin-4-ylamino)-pyrimidin-5-yl]- (2,3-difluore-6-metho:zy-phenyl)-methanone (Ezample 313), rac-4-[4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]-1- methanesulfonyl-piperidin-3-one (Example 314), oo 25 1-[4-[4-amino-5-(2-methoxy-5-methyl-benzoyl)-pyrimidin-2 -ylamino] -piperidin-1-yl]- ethanone (Example 326), [4-amino-2-( 1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(2-methoxy:5- methyl-phenyl)-methanone (Example 327), . CL I i ’

-34- oo : (4-amino-2-ethylsulfanyl-pyrimidin-5-y1)-(2,5-dimethoxy-phenyl)-methanone (Example 328),

: 1-[4-[4-amino-5-(2,5-dimethoxy-benzoyl)-pyrimidin-2-ylamino] -piperidin-1 1] - ethanone (Example 330), [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(2,5-dimethoxy- phenyl)-methanone (Example 331), 1-[4-[4-amino-5-(2,6-dimethoxy-benzoyl)-pyrimidin-2-ylamino}-piperidin-1 -yl}- ethanone (Example 334),

[4-amino-2-( 1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,6-dimethoxy-

phenyl)-methanone (Example 335), oT 1-[4-{4-amino-5-(5-fluoro-2-methoxy-4-methyl-benzoyl)-pyrimidin-2-ylamino]- piperidin-1-yl]-ethanone (Example 342), : [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl}-(5-fluoro-2- methoxy-4-methyl-phenyl)-methanone (Example 343),

[4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(3-fluoro-2,6- dimethoxy-phenyl)-methanone (Example 348), h [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2-ethoxy-3- fluoro-6-methoxy-phenyl)-methanone (Example 349), 1-[4-[4-amino-5-(3-fluoro-6-methoxy-2-methyl-benzoyl)-pyrimidin-2-ylamino]-

piperidin-1-yl]-ethanone (Example 351), [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(3-fluoro-6- methoxy-2-methyl-phenyl)-methanone (Example 352), 1-[4-(4-amino-5-(4-methyl-benzoyl)-pyrimidin-2-ylamino]-pipzridin-1-y1}-ethanone (Example 355),

[4-amino-2-( 1-methanesulfonyl- piperidin-4-ylamino)-pyrimidin-5-yl] -p-tolyl- methanone (Example 356), 1-(4-[4-amino-5-(4-methoxyl-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl] -etharione (Example 359), Co a.

CL ; To os Co

-35- oo [4-amino-2-(1 -methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(4-methoxy- phenyl)-methanone (Example 360), 1-[4-[4-amino-5-(4-chloro-benzoyl)-pyrimidin-2-ylamino} -piperidin-1-yl] -ethanone (Example 363), ‘ [4-amino-2-(1 methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(4-chloro- phenyl)-methanone (Example 364), 1-{4- [4-amino-5-(4-fluoro-benzoyl)-pyrimidin-2-ylamino) -piperidin-1-yl}-ethanone (Example 367), [4-amino-2-(1 -methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(4-fluoro-

phenyl)-methanone (Example 368), oT [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl}-(5-fluoro-2,4- dimethoxy-phenyl)-methanone (Example 369), : (4-amino-2-(1 -methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl}-(4-ethoxy-5- fluoro-2-methoxy-phenyl)-methanone (Example 370),

[4-amino-2-(1 -methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(3-fluoro-4- methoxy-phenyl)-methanone (Example 373), 4-[4-amino-5-( 5-fluoro-2-methoxy-4-methyl-benzoyl)-pyrimidin-2-ylamino] - piperidine-1-carboxylic acid tert-butyl ester (Example 374), [4-amino-2-(1 -methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(4-chloro-5- fluoro-2-methoxy-phenyl)-methanone (Example 378), y [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl}-(3,5-difluoro-2- methoxy-phenyl)-methanone (Example 381), [4-amino-2-( 1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl)-(2-fluore-5- methoxy-4-methyl-phenyl)-methanone (Example 335), and

[4-amino-2-( -methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-( 5-fluoro-2- } methoxy-3-methyl-phenyl)-methanone (Example 388).

Claims

- 264 - Co : CLATMS

1. A compound of the formula NH, O N™ XY R2 Mo i) N 1 R I ** wherein 5s R' is selected from the group consisting of SE heterocycle and lower alkyl-heterocycle, wherein the heterocycle moiety in both instances optionally may be substituted by up to four substituents independently © selected from : H, lower alkyl, lower alkyl substituted by oxo, OR", COR", NR’R®, S(O),R"’ or C(O)NR’R’, . COR’, COR", CORY, : C(O)NRVR™, : S(O)R", 0X0, OR'?, or : NR’R% : : aryl; aryl substituted by ~~ - H, -5(0)a-R", a . NR°R’, carbonyl, : oo _ RE ) carbonyl substituted by lower alkyl, OR? or NR’R®, AVE lower alkyl, = . Co Co oo oo _ : lower alkyl substituted by ORY or NR°RS, } : Ls

-265- SE OR’, or Halogen; : : cycloalkyl; . cycloalkyl substituted by OR’, NR°R® or S(O).R"> : lower alkyl; and lower alkyl substituted by NR°R’, y NR'"SO,R",

CO.RY, : S(O)R", | oo heterocycle, heterocycle substituted by lower alkyl, COR" or SOR", heteroaryl, heteroaryl substituted by : lower alkyl, CO;RY, or : SOR, } aryl, and : aryl substituted by BN lower alkyl, halogen, NRRS, CORY, or : CORY; R* is selected from the group consisting of ; aryl, heteroaryl, cycloalkyl and heterocycle, wherein each may be substituted by up to four substituents independently selected from the group consisting of, ~~ ~~ loweralkyl, SE ; lower alkyl substituted by halogen or ORY, = SE

-266- SE halogen, OR! NO,, CN, NR°R%, $(0),-R’, and SO,-NR*RY; . R’ and R® are each independently selected from the group consisting of . H; lower alkyl; lower alkyl substituted by oxo, CO;R", OR'?, NRR", C(O)NR"R", SOR", NSO,R'?, heteroaryl, heterocycle, or heterocycle substituted by oxo; "cycloalkyl; cycloalkyl substituted by CO,R'2, OR'2, NR" R*, C(O)NR"R™ or SOR" aryl; aryl substituted by NR'*R™, OR'2, CO,R'2, C(O)NR¥R™, SO,R"*, halogen, lower alkyl, or lower alkyl substituted by halogen, OR", oxo, CO,R'%, C(O)NR"R" or NRIR . SOR; CORY; .. COR'* and OR™ Rio 0) ~ o AO . or alternatively, -NR°R® can form a ring having 3 to 7 ring atoms, said ring optionally including one or more additional N or O ring atoms or the group SO, and optionally being substituted by OH, oxo, NR" R!4, lower alkyl and lower alkyl substituted by OR; R” is selected from the group consisting of | Co . - ’ . : Co

-267- Co Hj; lower alkyl; : lower alkyl substituted by OR', COR", NRR®, or C(O)NR’R® ) halogen; : 0X03 : aryl; N aryl substituted by up to three substituents independently selected from lower alkyl, halogen and NR°R® cycloalkyl; oo cycloalkyl substituted by OH, oxo, or NH,,

SO.R'¥ and COR"; R® is selected from the group consisting of ~ H; lower alkyl; lower alkyl substituted by NR'R® heterocycle; and . heterocycle substituted by lower alkyl, CO;R” or SOR"; R® is selected from the group consisting of H; and lower alkyl; RI js selected from the group consisting of | . lower alkyl; aryl; and aryl substituted by halogen or NR’R® . ~ : RI! is selected from the group consisting of. oo ; nL Er v. - a. H; lower alkyl; and lower alkyl substituted by oxo or halogen: : g | :

-268- oo Ris selected from the group consisting of H; lower alkyl; and lower alkyl substituted by NR’R® or OR"; R'’ and R™ are each independently selected from the group consisting of . H; ’ . lower alkyl; : lower alkyl substituted by CO,R", OR'%, NR’R®, C(O)NR’R?, SOR", NSO.R", . heteroaryl, heterocycle, or heterocycle substituted by oxo; cycloalkyl; a cycloalkyl substituted by CO,R'%, OR", NR°R®, C(O)NR’R® or SOR; aryl; : aryl substituted by NR’R®, OR'2, CO,R'?%, CONR’R’, SOR", halogen, lower alkyl, and lower alkyl substituted by halogen, OR'?, oxo, CO,R"?, C(O)NRR® or NR’R* SO2R'

CO.RY; COR; and OR?2 : Rito oO ~~ b AO or alternatively, -NR”’R* can form a ring having 3 to7 ring atoms, said ring optionally including one or more additional N or O ring atoms and optionally being substituted by OH, oxo, NR’R®, lower alkyl and lower alkyl substituted by OR'%; . 20 RY is selected from the group consisting of aryl; ’ aryl substituted by the group halogen, CO,R'?, SOR, COR" , lower alkyl and lower alkyl substituted by halogen, OR'?, oxo, COR", C(O)NR’R® or NR°R; heteroaryl; Co - : Co RE EEE

PCT/EP2004/000971 heteroaryl substituted by the group halogen, CORY, SO,RY, COR, lower alkyl and lower alkyl substituted by halogen, OR'?, oxo, CO,R'%, C(O)NR’R® or NR°R%; NRR; lower alkyl; lower alkyl substituted by halogen, OR'?, oxo, CO;R*, C(O)NR’R® or NR°RS; heterocycle, and heterocycle substituted by the group CORY, CORY, SO,R'?, COR"? Jower alkyl, C(O)NR°RSor NR°R®; R!6 and RY are each independently selected from the group consisting of H; and lower alkyl; or, alternatively, the group ~NR'RY can form a ring having 3 to 7 ring atoms, said ring optionally including one or more additional N or O ring atoms and optionally being substituted by lower alkyl, OH, oxo and NH; and n is0, 1 or2; or the pharmaceutically acceptable salts or esters thereof.

2. The compound of formula I of claim 1 wherein R! is selected from the group consisting of heterocycle and lower alkyl-heterocycle, wherein the heterocycle moiety in both instances optionally may be substituted by up to four substituents independently selected from H, lower alkyl, lower alkyl substituted by OR'2, COR", NR'R® or C(O)NR’R’, COR’, CORY, COR", C(O)NRPRY, S(O)R", AMENDED SHEET

-270 - oo 0X0, OR", or NR°RS; aryl; ‘ aryl substituted by H, -S(0)a-RY, NR’R’, carbonyl, carbonyl substituted by lower alkyl, OR? or NR’RS, lower alkyl, Co lower alkyl substituted by ORY or NR’R®, OR%, or Halogen; cycloalkyl; cycloalkyl substituted by OR’, NR°R® or S(O).R™ lower alkyl; and ~ lower alkyl substituted by - NR’R®, NR''SO;RY,

CO.R', S(0)aR", heterocycle, - heterocycle substituted by lower alkyl, COR? or SOR”, heteroaryl, heteroaryl substituted by lower alkyl, CO,R*, or SO,RY,

: . aryl, and ) aryl substituted by lower alkyl, halogen, NR°R®, COR", or COR"; R® is selected from the group consisting of ) . BEEN TERA aryl, heteroaryl, cycloalkyl and heterocycle, wherein €ach may be substituted by up

: . to four substituents independently selected from the group consisting of

-271- So - lower alkyl, _ lower alkyl substituted by halogen or ORY, halogen, ’ ORY? NO,, * CN, : NR’R’, : S(0)n-R’, and :

SO.-NR'*RY;

10 .,R® and R® are each independently selected from the group consisting of lower alkyl; lower alkyl substituted by COR’, OR'2, NR" R*, C(O)NR"R"*, SOR", : NSO,R'?, heteroaryl, heterocycle, or heterocycle substituted by oxo; cycloalkyl; cycloalkyl substituted by CO,R'?, OR'%, NRPR™ , C(O)NRR* or SO,R'™ aryl; : aryl substituted by NRPR', OR'2, CO,R", C(O)NRPR™, SOR", halogen, lower alkyl, or lower alkyl substituted by halogen, OR'2, oxo, CO,RY, C(O)NRPR" or NRER4

SO.R'; . CO:R'% COR" and OR? RM oO ~~ 5 0° ) or alternatively, -NR’R® can form a ring having 3 to.7 ring atoms, said ring optionally including one or more additional N or O ring atoms or the group $0,, arid optionally ; being substituted by OH, oxo, NRPR", lower alkyl and lower alkyl substituted by OR'%;

a2 _— Ris selected from the group consisting of H; lower alkyl; , lower alkyl substituted by OR, CO,R'?, NR°R®, or C(O)NR’R® halogen; : 0X0; * aryl; : aryl substituted by up to three substituents independently selected from lower alkyl, halogen and NR’R® cycloalkyl; : cycloalkyl substituted by OH, oxo, or NH,

SO.R'* and COR"; R® is selected from the group consisting of . H; lower alkyl; lower alkyl substituted by NERS heterocycle; and - heterocycle substituted by lower alkyl, CO,R22 or SOR? > R? is selected from the group consisting of H; and lower alkyl; RY is selected from the group consisting of . lower alkyl; aryl; and aryl substituted by halogen or NR°R® . : RYis selected from the group consisting of BE ) ] ) } ; a - ia } : ; H; and lower alkyl; oo | - os )

-273- CL R'?is selected from the group consisting of H; lower alkyl; and lower alkyl substituted by NRR® or ORY; R'® and RM are each independently selected from the group consisting of i. lower alkyl; | : lower alkyl substituted by CO;R'%, OR'2, NR’R®, C(O)NRR®, SOR”, NSO,R'?, “ heteroaryl, heterocycle, or heterocycle substituted by oxo; cycloalkyl; CL : cycloalkyl substituted by CO,R'2, OR™, NRR®, C(O)NR’R® or SO,R"; aryl; : aryl substituted by NR°R®, OR'?, CO.R'2, CONR’R’, SO,R", halogen, lower alkyl, and lower alkyl substituted by halogen, OR, oxo, CORY, C(O)NR’R® or NR°R® SOR; COR : COR'%; and : OR12 : RO Oo ~ 5 =O or alternatively, -NR'>R"* can form a ring having 3 to7 ring atoms, said ring optionally including one or more additional N or O ring atoms and optionally being substituted by OH, oxo, NR’R®, lower alkyl and lower alkyl substituted by OR"; : 20 RY is selected from the group consisting of aryl; ’ aryl substituted by the group halogen, CORY, SO,R®, COR" , lower alkyl and lower alkyl substituted by halogen, OR", oxo, COR'2, C(O)NR’R® or NR R% heteroaryl; CY ] Lo _ EEE

-274- Co heteroaryl substituted by the group halogen, COR", SOR, COR, lower alkyl and lower alkyl substituted by halogen, OR", oxo, COR", C(O)NR’R® or NR°R; NRR; : A lower alkyl; lower alkyl substituted by halogen, OR"? oxo, CORY, C(O)NR’R® or NR°Ré; heterocycle, and heterocycle substituted by the group CO,R'2, COR! 2 SO,R', COR" lower alkyl, C(O)NR’R®or NR°R’; R'® and RY are each independently selected from the group consisting of H and lower alkyl; or, alternatively, the group ~NR'R" can form a ring having 3 to 7 ring atoms, said ring : optionally including one or more additional N or O ring atoms and optionally being substituted by lower alkyl, OH, oxo and NH; and n 1s0,1 or 2; or the pharmaceutically acceptable salts or esters thereof.

3. The compound of formula I of claim 1 or claim 2, wherein R? is phenyl.

4. The compound of formula I of claim 1 or claim 2, wherein R? is phenyl substituted by halogen or OR'%, and R'? is lower alkyl.

5. The compound of formula I of claim 4, wherein the halogen is F and the R"% is methyl.

6. The compound of formula I of claim 1, wherein R! is selected from Ge 1 N° Lge | TRE oo (a), EC RE EAN CE

S275. SE R4 R4 ¢ R* N : \ AN R3 RS RS OR? (d), (e)s 0, R® | R* R# Nel 0) S(O), AN L s RS R6 : (8) R® (h),and <i), wherein R® is selected from the group consisting of H, oe lower alkyl, ] lower alkyl substituted by oxo, OR, COR, NR’R®, SO,R'” or C(O)NR’RS,

CO.R’, COR", : : C(O)NR’R’, and SOR"; R* is selected from the group consisting of : : H, lower alkyl, NR’R® ’ NO, RY 0X0 ) CN, and Co N . halogen; E . EE ) RY is selected from the group consisting of ~~ - -.o. oo a. So

: ’ PCT/EP2004/000971

ORY, lower alkyl, NR°RS, NO, CN, and halogen; R’and R® are each independently selected from the group consisting of H, lower alkyl, lower alkyl substituted by oxo, CO:R'%, OR”, NR" RY, C(O)NRU RM, SOR, NSO,R'?, heteroaryl, heterocycle, or heterocycle substituted by oxo, cycloalkyl, cycloalkyl substituted by CO;R", OR", NRE RM, C(O)NR¥R™ or SO;R”, aryl, aryl substituted by NR¥R™, OR'%, CO,R", C(O)NRVR", SO:R", halogen, lower alkyl, and lower alkyl substituted by halogen, OR'2, oxo, CO;R', C(O)NRPR'* and NRPPRY; SO:RY, COR", COR", and OR12 RYO - | 0 or alternatively, -NR® RS can form a ring having 3 to 7 atoms, said ring optionally including one or more additional N or O atoms and optionally being substituted by OH, oxo, NR"’R'*, lower alky! and lower alkyl} substituted by OR'%; Ris selected from the group consisting of H, lower alkyl, lower alkyl substituted by OR'?, COR, NR°R®, or CONR’RS, halogen, oxo, aryl, aryl substituted by up to three substituents independently selected from lower alkyl, halogen, and NRR®, cycloalkyl, AMENDED SHEET

: “277 a cycloalkyl substituted by OH, oxo, or NH,, SOR", and COR; R® is selected from the group consisting of . 5 H, lower alkyl, : lower alkyl substituted by NR°R®, : heterocycle, and heterocycle substituted by lower alkyl, CO,R" or SO,R3; R' isselected from the group consisting of lower alkyl, aryl, and aryl substituted by halogen or NR°RS;.. - R'is selected from the group consisting of H, lower alkyl, and lower alkyl substituted by oxo and halogen; Ris selected from the group consisting of H, lower alkyl, and lower alkyl substituted by halogen, oxo, NR’R® or OR"); R” and R™ are independently selected from the group consisting of H, lower alkyl, lower alkyl substituted by CO,R'%, OR'?, NR°R®, C(O)NR’R’, SOR", NSO,R™2, heteroaryl, heterocycle, or heterocycle substituted by oxo, cycloalkyl, . cycloalkyl substituted by CO,R', OR', NR°R®, C(O)NR®R® or SO,R", aryl, aryl substituted by NR°R®, OR", CO,R', C(O)NRR?, SOR", halogen, lower alkyl, and lower alkyl substituted by halogen, ORY, oxo, CORY, C(O)NR’R® and NR°RS;

SO.R", CORY, COR", and OR?2

RYO. : or alternatively, -NR"R" can form a ring having 3 to 7 ring ators, said ring optionally, including one or more additional N or O ring atoms and optionally being substituted by - OH, oxo, NR’R’, lower alkyl and lower alkyl substituted by OR'%" . ST

-278- oo R™ is selected from the group consisting of oo aryl, aryl substituted by the group halogen, COR, SO,R'?, CORY, lower alkyl and ’ lower alkyl substituted by halogen, OR", oxo, CORY, C(O)NR’R® or NR°R®, heteroaryl, ° : heteroaryl substituted by the group halogen, CO,R", SO,R*®, COR", lower alkyl and lower alkyl substituted by halogen, OR", oxo, CO,R'?, C(O)NR’R® or NR’R’, NRR’, lower alkyl, lower alkyl substituted by the group halogen, OR'?, oxo, CO,R", C(O)NR’R® or * NR°R® : heterocycle, and oo heterocycle substituted by the group COR, CORY, SO,R'2, lower alkyl C(O)NR’R® or NR°RS; X isselected from the group consisting of ‘ S, SO, SO, and O; and n is0, 1 or 2; or the pharmaceutically acceptable salts or esters thereof.

7. The compound of formula I of claim 6 having the formula NH, O R21 N ~~ R18 "R20 NS | R HN RIS Cr : I(@), R® wherein R® and R* are as defined in claim 6 and R! RY RY and R* areeach ) independently selected from lower alkyl, halogen and OR. :

8. The compound of formiila I(a) of claim 7, wherein R® is selected from the group consisting of COR’, COR"? and SO,R” and R’, R”? and R"® are as defined in claim 6.

-279 - a

9. The compound of formula I(a) of claim 8, wherein R’,R*? and R*® are hydrogen or lower alkyl. ' 10. The compound of formula I(a) of claim 8, wherein R? is SO,RY and R¥ is lower alkyl or NR’RS. «

11. The compound of formula I(a) of claim 7 selected from the group consisting of 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1- carboxylic acid ethyl ester, - 4-[4-amino-5-(2,6-difluoro-benzoyl)-pyrimidin-2-ylamino] -piperidine-1- carboxylic acid ethyl ester, 4- [4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2 _ylamino] -piperidine-1- carboxylic acid ethyl ester, . 1-[4- [4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino] -piperidin-1-yl]- ethanone, 1-[4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino} -piperidin-1 -yl}- propan-l-one, oo 1-[4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1 -yl]- butan-1-one, 1-[4- [4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino] -piperidin-1-yl]-3- methyl-butan-1-one, 1-[4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl}-3- diethylamino-propan-1-one, 4-[4-amino-5-(2-methyl-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid ethyl ester, 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1- carboxylic acid methyl ester, ) 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino] -piperidine-1- carboxylic acid propyl ester, Co RA : 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1: a carboxylic acid iso-butyl ester, Co Ce

: PCT/EP2004/000971

4-[4-amino-5-(2-methoxy-benzoyl) -pyrimidin-2-ylamino]-piperidine-1- carboxylic acid methylamide, 4- [4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1- carboxylic acid ethylamide, 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1- carboxylic acid propylamide, [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2- methoxy-phenyl)-methanone, [4-amino-2-(1-ethanesulfonyl-piperidin -4-ylarnino)-pyrimidin-5-yl]- (2-methoxy- phenyl)-methanone, [4-amino-2-[1-(propane-1 _sulfonyl)-piperidin-4-ylamino] -pyrimidin-5-y1}-(2- methoxy-phenyl)-methanone, 1-[4- [4-amino-5-(5-fluoro-2-methoxy-benzoyl) -pyrimidin-2-ylamino]-piperidin- 1-yl]-ethanone, 4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino] -piperidine-1- carboxylic acid methyl ester, 4- (4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino] -piperidine-1- carboxylic acid propyl ester, 1-[4- [4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino] -piperidin- 1-yl]-propan-1l-one, 1-[4- [4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino] -piperidin- 1-yl]-butan-1-ons, 4-[4-amino-3-(2-methoxy-benzoyl) -pyrimidin-2-ylamino] -piperidine-1- carboxylic acid dimethylamide, [4-amino-2-( 1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(3-fluoro- 2-methoxy-phenyl)-methanone, [4-amino-2-(1 ethanesulfonyl-piperidin-4-ylamino)-pyrimidin-3-yll -(5-fluoro-2- methoxy-phenyl)-methanone, AMENDED SHEET

-281- oo [4-amino-2-{i-(propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5- fluoro-2-methoxy-phenyl)-methanone, : [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(2-fluoro- phenyl)-methanone, [4-amino-2-(1-ethanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2-fluoro- phenyl)-methanone, 4-[4-amino-5-(2-fluoro-benzoyl)-pyrimidin-2-ylamino}-piperidine-1-carboxylic acid ethyl ester, [4-amino-2-(1-trifluoromethanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl}- (5-fluoro-2-methoxy-phenyl)-methanone, - A 4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino] -piperidine-1- -

a. sulfonic acid dimethylamide, 1-{4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino}-piperidin- - .- - 1-yl}-2-dimethylamino-ethanone, AEE co 1-[4-]4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino) -piperidin- : . - : 1-yl]-2-diethylamino-ethanone, En eo 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino) -piperidin- - : 1-y1]-2-morpholin-4-yl-ethanone, . Co ol 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino) -piperidin- " : 20 1-yl]-3-dimethylamino-propan-1-one, Ce 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino}-piperidin- 1-yl]-3-diethylamino-propan-1-one, 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin- 1-yl]-3-piperidin-1-yl-propan-1-one, oo 25 © 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino] -piperidin- : 1-y1]-3-morpholin-4-yl-propan-1-one, ’ [4-amino-2-[1-(3,5-dimethyl-isoxazole-4-sulfonyl)-piperidin-4-ylamino]- Ce hs pyrimidin-5-y1]-(5-fluoro-2-methoxy-phenyl)-methanone. ) K vo N oo

282- SE (4: [4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino] -piperidin-1- yl]-acetic acid methyl ester, 1-[4- [4-amino-5-(2,6-difluoro-3-methoxy-benzoyl)-pyrimidin-2-ylamino) - piperidin-1-yl}-ethanone, [4-amino-2-( I-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(2,6- difluoro-3-methoxy-phenyl)-methanone, 4-[4-amino-5-(2,6-difluoro-3-methoxy-benzoyl)-pyrimidin-2-ylamino]- piperidine-1-carboxylic acid methyl ester, : : 1-[4-[4-amino-5-(2-ethoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1 -yli- : ethanone, - [4-amino-2-[1-(thiophene-3-sulfonyl)-piperidin-4-ylamino] -pyrimidin-5-yl}-(5- fluoro-2-methoxy-phenyl)-methanone, : Co : oo [4-amino-2-[1-(benzo[b] thiophene-3-sulfonyl)-piperidin-4-ylamino]-pyrimidin-- 5-yl}-(5-fluoro-2-methoxy-phenyl)-methanone, Co [4-amino-2-[1-( 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)-piperidin-4-ylamino] - pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone, . - 3-[4- (4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino] - : ’ piperidine-1-sulfonyl]-thiophene-2-carboxylic acid methyl ester, and CL : : [4-amino-2-[1-(2,5-dimethyl-thiophene-3-sulfonyl)-piperidin-4-ylamino]- pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone, CL 4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino}-piperidine-1- carboxylic acid cyclohexylamide, 1-[4-[4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino}- piperidin-1-yl]-ethanone, : (4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)- pyrimidin-5-y1]-(2,3- - difluoro-6-methoxy-phenyl)-methanone, ’ [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)- Ce methanone, So — cL Lo . CT

-283- oo (4-amino-2- (piperidin-4-ylamino)-pyrimidin-5-yl] -(5-fluoro-2-methoxy-phenyl)- methanone, . [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy- phenyl)-methanone, 1-[4~[4-amino-5-(2,3,4-trifluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]- : piperidin-1-yl]-ethanone, : [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl)-(3,4,5- trifluoro-2-methoxy-phenyl)-methanone, : [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-y1]-(2,3,4- trifluoro-6-methoxy-phenyl)-methanone, Sons : [4-amino-2-[1-(2-methanesulfonyl-ethyl)-piperidin-4-ylamino] -pyrimidin-5-yl]- (5-fluoro-2-methoxy-phenyl)-methanone, 1-[4-[4-amino-5-(5-fluoro-2-methyl-benzoyl)-pyrimidin-2-ylamino]-piperidin-1- . - yl]-ethanone, : [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro- 2-methyl-phenyl)-methanone, So : [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro- 2-trifluoromethyl-phenyl)-methanone, Ce [4-amino-2-( 1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(5-fluoro- 2-isopropoxy-phenyl)-methanone, (4-amino-2-(1 -methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-y1] -(2-ethoxy- 5-fluoro-phenyl)-methanone, [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2-ethyl-5- fluoro-phenyl)-methanone, Co 25 [4-amino-2-(1-methanesulfonyl-piperidin-4-ylaming)-pyrimidin-5-yl}-(2- methoxy-4-trifluoromethyl-phenyl)-methanone, 4-[4-amino-5-(2-fluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]-pipéridine-1- carboxylic acid tert-butyl ester, SE So EL

_284- Co [4-amino-2- (piperidin-4-ylamino)-pyrimidin-5-yl] -(2-fluoro-6-methoxy-phenyl)- methanone, [4-amino-2-( 1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-y1] -(2-fluoro- 6-methoxy-phenyl)-methanone, 1-[4- [4-amino-5-(2-fluoro-6-methoxy-benzoyl) _pyrimidin-2-ylamino) -piperidin- 1-y1]-2,2,2-trifluoro-ethanone, (4-amino-2-[1-(3-chloro-propane- 1-sulfonyl)-piperidin-4-ylamino] -pyrimidin-5- yl] -(2,3-difluoro-6-methoxy-phenyl)-methanone, (4-amino-2-[1-[3-(2-hydroxy- 1-methyl-ethylamino)-propane-1 -sulfonyl]- : piperidin-4-ylamino]-pyrimidin-5-y1)-(23-difluoro-6-methoxy-phienyl)-methanone, (4-amino-2-[1-[3-(4-methyl-piperazin-1-yl)-propane-1-sulfonyl] -piperidin-4- ylamino)-pyrimidin-5-yl)- (2,3-difluoro-6-methoxy-phenyl)-methanone, (4-amino-2-[1- (3-((R)-1-hydroxymethyl-propylamino)-propane- 1-sulfonyl]- piperidin-4-ylamino] -pyrimidin-5-y1)- (2,3-difluoro-6-methoxy-phenyl) -methanone, _ 15 '4-ammino-2-[1-(3-hydroxy-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin- 5-yl}-(2,3-difluoro-6-methoxy-phenyl)-methanone, [4-amino-2-[1-(3-pyrrolidin- 1-yl-propane-1 _sulfonyl)-piperidin-4-ylamino] - pyrimidin-5-y1}-(2,3-difluoro-6-methoxy-phenyl)-methanone, SL : (4-amino-2-{1 _(3-morpholin-4-yl-propane- 1 _sulfonyl)-piperidin-4-ylamino] - pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone, [4-amino-2-(1-[3-[4- (2-hydroxy-ethyl)-piperazin- 1-yl]-propane-1-sulfonyl]- piperidin-4-ylamino)-pyrimidin-5-yl] - (2,3-difluoro-6-methoxy-phenyl) -methanone, {4-amino-2-(1-[3-[(2-methoxy-cthyl)-methyl-amino]-propane-1-sulfonyl]- piperidin-4-ylamino) -pyrimidin-5-yl] -(2,3-difluoro-6-methoxy-phenyl)-methanone, (4-amino-2-{1-[3-(2-hydroxy-1,1-dimethyl-ethylamino)-propane-1-sulfonyl)- . piperidin-4-ylamino] pyrimidin-5-y1)-(2,3-difluoro-6-methoxy-phenyl) -methanone, (4-amino-2-[1- [3-(2-hydroxy-propylamino)-propane- 1-sulfonyl]-piperidin-4- Jlamino]-pyrismidin-5-yD-(2,3-difluoro-6-methoxy-phenyl-methanonie : NB Lo

- 285 - So (4-amino-2-[1-[3-((S)-2-hydroxy- 1-methyl-ethylamino)-propane-1 -sulfonyl]- piperidin-4-ylamino)-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone, ) (4-amino-2-[1-[3-((R)-1 -hydroxymethyl-2-methyl-propylamino)-propane-1 - sulfonyl] -piperidin-4-ylamino]-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)- : 5 methanone, (4-amino-2-[1-[3-((R)-2-hydroxy-1-methyl-ethylamino)-propane- 1-sulfonyl] - piperidin-4-ylamino]-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone, (4-amino-2-{1-[3-((S)-1 -hydroxymethyl-propylamino)-propane-1-sulfonyl]- * piperidin-4-ylamino]-pyrimidin-5-yl)- (2,3-difluoro-6-methoxy-phenyl)-methanone,

[4-amino-2-(1-[3-[3-hydroxy-1-(2-hydroxy-ethyl)-propylamino]-propane-1- sulfonyl]-piperidin-4-ylamino)-pyrimidin-5-yl}-(2,3-difluoro-6-methoxy-phenyl)- methanone,

~~ [4-amino-2-[ 1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino] -pyrimidin-5- yl] -( 5-fluoro-2-methoxy-phenyl)-methanone, :

[4-amino-2-(1-[3-[ (2-methoxy-ethyl)-methyl-amino]-propane-1-sulfonyl}- : piperidin-4-ylamino)-pyrimidin-5-y1}-(5-fluoro-2-methoxy-phenyl)-methanone,

[4-amino-2-(1-(3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propane-1-sulfonyl]- piperidin-4-ylamino)-pyrimidin-5-yl] -(5-fluoro-2-methoxy-phenyl) -methanone, (4-amino-2-[1-[3-((S)-2-hydroxy-1-methyl-ethylamino)-propane-1 -sulfonyl}- piperidin-4-ylamino}-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone, (4-amino-2-[1-[3-((R)-1-hydroxymethyl-propylamino)-propane-1-sulfonyl]- piperidin-4-ylamino] -pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone, (4-amino-2-[1-[3-(2-hydroxy-propylamino)-propane-1-sulfonyl]-piperidin-4- ylamino]-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone, (4-amino-2-{1-[3-((R)-1-hydroxymethyl-2-methyl-propylamino)-propane-1- sulfonyl] -piperidin-4-ylamino]-pyrimidin-5-yl)- (5-fluoro-2-methoxy-phenyl)- : methanone, (4-amino-2-[1-3-(2-methoxy- 1-methyl-ethylamino)-propane-1 -sulfonyl]- - - . piperidin-4-ylamino]-pyrimidin-5-yl) -(5-fluoro-2-methoxy-phenyl) -metharione, Co

-286- a (4-amino-2-[1-[3-(2-hydroxy-1 ,1-dimethyl-ethylamino)-propane-1-sulfonyl] - piperidin-4-ylamino]-pyrimidin-5-y1)-(5-fluoro-2-methoxy-phenyl)-methanone, (4-amino-2-[1-[3-((R)-2-hydroxy-1-methyl-ethylamino)-propane-1-sulfonyl]- piperidin-4-ylamino]-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone, (4-amino-2-[1-[3-((S)-1-hydroxymethyl-propylamino)-propane-1-sulfonyl}- piperidin-4-ylamino]-pyrimidin-5-y1)-(5-fluoro-2-methoxy-phenyl)-methanone, [4-amino-2-[1-(4-hydroxy-butane-1-sulfonyl)-piperidin-4-ylamino} -pyrimidin-5- yl]-(5-fluoro-2-methoxy-phenyl)-methanone, [4-amino-2-[1-(4-chloro-butane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5- yl]-(5-fluoro-2-methoxy-phenyl)-methanone, Sod ' (4-amino-2-[1-[4-(4-methyl-piperazin-1-yl)-butane-1-sulfonyl] -piperidin-4- ylamino]-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone, : [4-amino-2-[1-(4-pyrrolidin-1-yl-butane- 1-sulfonyl)-piperidin-4-ylamino}- pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone, : (4-amino-2-[1- [4-(2-hydroxy-propylamino)-butane- 1-sulfonyl]-piperidin-4- ylamino]-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone, [4-amino-2-(1 _methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(2,3- ~ difluoro-5,6-dimethoxy-phenyl)-methanone, Co [4-amino-2-(1 _methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(2,3- difluoro-6-hydroxy-5-methoxy-phenyl)-methanone, (4-amino-2-(1 -methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl} -(2,3- difluoro-5,6-dihydroxy-phenyl)-methanone, [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl}-(2,3- difluoro-5-hydroxy-6-methoxy-phenyl)-methanone, Co 25 © [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino] -pyrimidin-5- y1]-(5-fluoro-2-methoxy-phenyl)-methanone, ’ ~ [4-amino-2-[1-(3-pyrrolidin-1-yl-propane-1 -sulfonyl)-piperidin-4-ylamiho}- - pyrimidin-5-y1]-(5-fluoro-2-methoxy-phenyl)-methanone, . B v Lo

287 - Co acetic acid 3-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]- piperidine-1-sulfonyl]-propyl ester, _ [4-amino-2-[1-(3-hydroxy-propane-1-sulfonyl)-piperidin-4-ylamino}-pyrimidin- 5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone, [4-amino-2-[1-(3-morpholin-4-yl-propane-1 -sulfonyl)-piperidin-4-ylamino] - pyrimidin-5-y1]-(5-fluoro-2-methoxy-phenyl)-methanone, N-(3-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]- piperidine-1-sulfonyl]-propyl)-methanesulfonamide, ) (4-amino-2-[1-[3-(4-methyl-piperazin-1-yl)-propane- 1-sulfonyl] -piperidin-4- ylamino)-pyrimidin-5-y1)-(5-fluoro-2-methoxy-phenyl)-methanone, [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-y1]-(2,3- difluoro-6-hydroxy-phenyl)-methanone, [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -phenyl- methanone, 4-[4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]- piperidine-1-carbaldehyde, - 4- [4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino] - piperidine-1-sulfonic acid amide, : : . 4- [4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]- piperidine-1-sulfonic acid acetyl-amide, rac-[4-amino-2-(3-hydroxy-1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin- 5-y1)-(2,3-difluoro-6-methoxy-phenyl)-methanone, rac-[4-amino-2-(3-hydroxy-1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin- 5-y1]-(2,3-difluoro-6-methoxy-phenyl)-methanone, Co 25 . rac-[4-amino-2-(1-methanesulfonyl-3-methoxy-piperidin-4-ylamino)-pyrimidin- } 5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone, rac-4-[4-amino-5- (2,3-difluoro-6-methoxy-benzoyl) -pyrimidin-2-ylamirfo] -1- methanesulfonyl-piperidin-3-one, Co I

-288- S 1-[4-[4-amino-5-(2-methoxy-5-methyl-benzoyl)-pyrimidin-2-ylamino] _piperidin- 1-yl]-ethanone, : ’ [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(2- methoxy-5-methyl-phenyl)-methanone, (4-amino-2-ethylsulfanyl-pyrimidin-5-y1)-(2,5-dimethoxy-phenyl)-methanone, 1-{4-[4-amino-5-(2,5-dimethoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1 -yl}- ethanone, » [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,5- dimethoxy-phenyl)-methanone, : 1-[4-[4-amino-5-(2,6-dimethoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1 -yl]- ethanone, [4-amino-2-( 1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin- 5-y1}-(2,6- dimethoxy-phenyl)-methanone, : 1-[4- [4-amino-5-(5-fluoro-2-methoxy-4-methyl-benzoyl)-pyrimidin-2-ylamino] - piperidin-1-yl]-ethanone, [4-amino-2-(1 -methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(5-fluoro- 2-methoxy-4-methyl-phenyl)-methanone, [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl}-(3-fluoro- 2,6-dimethoxy-phenyl)-methanone, [4-amino-2-(1 —methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2-ethoxy- 3-fluoro-6-methoxy-phenyl)-methanone, 1-[4- [4-amino-5-(3-fluoro-6-methosy-2-methyl-benzoyl)-pyrimidin-2-ylamino} - ~ piperidin-1-yl]-ethanone, . [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(3-fluoro- 6-methoxy-2-methyl-phenyl)-methanone, 1-[4-[4-amino-5-(4-methyl-benzoyl)-pyrimidin-2-ylamino] -piperidin-1-yl]- ethanone, oo Co : _ - IR {4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrirhidin-5-ylJ:p-tolyl- . methanone, . oo ] EEE oo -280- oo 1-[4-[4-amino-5- (4-methoxyl-benzoyl)-pyrimidin-2-ylamino]-piperidin-1 yl] ethanone, : [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(4- methoxy-phenyl)-methanone, 1-[4~[4-amino-5-(4-chloro-benzoyl)-pyrimidin-2-ylamino] -piperidin-1-yl]- ethanone, [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-y1]-(4-chloro- _ phenyl)-methanone, 1-[4~(4-amino-5-(4-fluoro-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-y1]- : ethanone, -e [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(4-fluoro- phenyl)-methanone, [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro- 2,4-dimethoxy-phenyl)-methanone, [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(4-ethoxy- 5-fluoro-2-methoxy-phenyl)-methanone, [4-Amino-2-( 1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(3-fluoro- 4-methoxy-phenyl)-methanone, 4-[4-amino-5-(5-fluoro-2-methoxy-4-methyl-benzoyl)-pyrimidin-2-ylamino]- piperidine-1-carboxylic acid tert-butyl ester, (4-amino-2-( 1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -(4-chloro- 5-fluoro-2-methoxy-phenyl)-methanone, : [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl}-(3,5- difluoro-2-methoxy-phenyl)-methanone, Co 25 : [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl}-(2-fluoro- 5-methoxy-4-methyl-phenyl)-methanone, and ; - [4-amino-2-( 1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl] -( 5-fluoro- 2-methoxy-3-methyl-phenyl)-methanone. = | So cL B cL CL . - ol

-290- a

12. The compound of formula I of claim 6 having the formula : NH, O R21 : NZ R18 20 , N | R : HN R19 RA4 i(e), N : RN RS R6 FRET wherein R%, R®, RS, R'8, RY, R?® and R*! are as defined in claim 6.

"13. The compound of formula I(e) of claim 12, wherein R*%, R'’, R? and R* are each independently selected from lower alkyl, halogen and OR? and R"?is hydrogen or lower alkyl.

14. The compound of formula I(e) of claim 12, wherein R® and R® are independently selected from H, COR" and SO,R*® and R*? and R"” are hydrogen or lower alkyl.

15. The compound of formula I(e) of claim 12 selected from the group consisting - of: trans-[4- [4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino] - cyclohexyl]-carbamic acid tert-butyl ester, B trans-|4-amino-2-(4-amino-cyclohexylamino)-pyrimidin-5-yl]-(5-fluoro-2- methoxy-phenyl)-methanone, trans-N-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino}- cyclohexyl] -acetamide, : N-[4-[4-amino-5-( 5-fluoro-2-methoxy-benzoyl-pyrimidin-2-ylamino] - cyclohexyl]-methanesulfonamide, . Co : ethanesulfonic acid [4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2- ylamino]-cyclohexyl]-amide, : EE SE FO

-291- SI (4-{4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino] cyclohexyl] - carbamic acid ethyl] ester, : [4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-cyclohexyl]- carbamic acid isopropyl ester, [4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-cyclohexyl}- carbamic acid 2-methoxy-ethyl ester, trans- N-[4-[4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]- cyclohexyl]-acetamide, trans- N-[4-[4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]- cyclohexyl]-methanesulfonamide, So trans-[4-amino-2-[4-(2-hydroxy-ethylamino)-cyclohexylamino]-pyrimidin-5-yl} - (2,3-difluoro-6-methoxy-phenyl)-methanone, trans-(4-amino-2-(4-[bis-(2-hydroxy-ethyl)-amino}-cyclohexylamino]-pyrimidin- 5-y1)-(2,3-difluoro-6-methoxy-phenyl)-methanone, trans-N-[4-[4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]- cyclohexyl ]-succinamic acid, - trans-3-chloro-propane-1-sulfonic acid [4- [4-amino-5-(2,3-difluoro-6-methoxy- benzoyl)-pyrimidin-2-ylamino]-cyclohexyl]-amide, : trans-3-morpholin-4-yl-propane-1-sulfonic acid [4-[4-amino-5-(2,3-difluoro-6- methoxy-benzoyl)-pyrimidin-2-ylamino]-cyclohexyl}-amide, trans-3-(4-methyl-piperazin-1-yl)-propane-1-sulfonic acid [4-[4-amino-5-(2,3- difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]-cyclohexyl]-amide, trans-3-pyrrolidin-1-yl-propane-1-sulfonic acid [4-[4-amino-5-(2,3-difluoro-6- methoxy-benzoyl)-pyrimidin-2-ylamino}-cyclohexyl]-amide, © trans-3-hydroxy-propane-1-sulfonic acid [4-[4-amino-5-(2,3-difluoro-6-methoxy- benzoyl)-pyrimidin-2-ylamino]-cyclohexyl]-amide, trans- (4-amino-2-(4-(1,1-dioxo-11’-isothiazolidin-2-yl)-cyclohexylamino]- - pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone, [EE

-202- Co ~ trans-[4-amino-2-[4-(4-methyl-piperazin- 1-yl)-cyclohexylamino]-pyrimidin-5- y1]-(2,3-difluoro-6-methoxy-phenyl)-methanone,. : trans-[4-amino-2-(4-pyrrolidin-1-yl-cyclohexylamino)-pyrimidin-5-yl] -(2,3- difluoro-6-methoxy-phenyl)-methanone, trans-{4-amino-2- (4-dimethylamino-cyclohexylamino)-pyrimidin-5-yl] -(2,3- difluoro-6-methoxy-phenyl)-methanone, [4-[4-amino-5-(2-methoxy-5-methyl-benzoyl)-pyrimidin-2-ylamino]-cyclohexyl]- carbamic acid tert-butyl ester, [4-amino-2-(4-amino-cyclohexylamino)-pyrimidin-5-yl]-(2-methoxy-5-methyl- phenyl)-methanone, EE N-[4-[4-amino-5-(2-methoxy-5-methyl-benzoyl)-pyrimidin-2-ylamino]- cyclohexyl] -acetamide, N-[4-[4-amino-5-(2-methoxy-5-methyl-benzoyl)-pyrimidin-2-ylamino]- cyclohexyl]-methanesulfonamide, [4-[4-amino-5-(5-fluoro-2-methoxy-4-methyl-benzoyl)-pyrimidin-2-ylamino}- cyclohexyl]-carbamic acid tert-butyl ester, [4-amino-2-(4-amino-cyclohexylamino) _pyrimidin-5-yl] -(5-fluoro-2-methoxy-4- methyl-phenyl)-methanone, N-[4- [4-amino-5-(5-fluoro-2-methoxy-4-methyl-benzoyl)-pyrimidin-2-ylamino] - cyclohexyl]-acetamide, and N-[4-[4-amino-5-(5-fluoro-2-methoxy-4-methyl-benzoyl)-pyrimidin-2-ylamino]- cyclohexyl]-methanesulfonamide.

16. The compound of formula I of claim 6 having the formula NH, O R21 : N= R18 20 ' PN | R HN R19 R# (9), N ON RS RS 7 wherein RY, R%, R®, R'%, R'’, R? and R* are as defined in claim 6.

"17. The compound of formula I(g) of claim 16, wherein R'8, RY, R® and R* are each independently selected from lower alkyl, halogen and OR".

18. The compound of formula I(g) of claim 16, wherein R* is selected from the group consisting of H, OR"! and lower alkyl and R'is hydrogen or lower alkyl.

19. The compound of formula I(g) of claim 16, wherein NRR® forms a ring having 3 to 7 ring atoms, said ring optionally including one or more additional N or O ring atoms and optionally being substituted by OH, oxo, NHy, lower alkyl and lower alkyl substituted by OR" and R* is hydrogen or lower alkyl.

20. The compound of formula I(g) of claim 16 selected from the group consisting of: B [4-amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-5-yl}-(3-

15. fluoro-phenyl)-methanone, [4-amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-5-yl}-(2- to methoxyphenyl)-methanone, : . [4-amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-5-yl]-(2,6- difluoro-phenyl)-methanone, ~ _ - : [4-amino-2-[4- (4-isopropyl-piperazin-1-y1)-phenylamino] -pyrimidin-5-y1] -(2- methoxy-phenyl)-methanone, CT } So So

[4-amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino)-pyrimidin-5-y]-(2,6- difluoro-phenyl)-methanone, . [4-amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-5-y1]-(5- fluoro-2-methoxy-phenyl)-methanone, ] 5 [4-amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-pyrimidin-5-yl]-(5- fluoro-2-methoxy-phenyl)-methanone, [4-amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-5-yl}-o-tolyl- methanone, ’ [4-amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-pyrimidin-5-yl}-o- tolyl-methanone, and ES 4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1- carboxylic acid (4-dimethylamino-phenyl)-amide.

21. A compound of formula I of claim 1, selected from the group [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]- (5-fluoro- 2-methoxy-phenyl)-methanone, y : trans-N-[4-[4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]- cyclohexyl]-methanesulfonamide, trans-N-[4-{4-amino-5-(5-fluoro-2-methoxy-benzoyl-pyrimidin-2-ylamino]- cyclohexyl]-methanesulfonamide, : [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2- methoxy-phenyl)-methanone, : : 1-[4-[4-amino-5-(5-fluoro-2-methoixy-benzoyl)-pyrimidin-2-ylamino] -piperidin- 1-yl]-ethanone, . ~ 1-[4-[4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino}- piperidin-1-yl]-ethanone and j . trans- N-[4-[4-Amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2- . : ylamino]-cyclohexyl] -acetamide. oo ) So Co

- 295 - Co

22. A compound of formula I of claim 1, whichis 1-[4-[4-amino-5-(5-fluoro-2- methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone.

23. A compound of formula I of claim 1, which is [4-amino-2-(1-methanesulfonyl- . piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone.

24. A compound of formula I of claim 1, which is [4-amino-2-(1-methanesulfonyl- piperidin-4-ylamino)-pyrimidin-5-yl}-(2,3-difluoro-6-methoxy-phenyl)-methanone. “ 25. A compound of formula I of claim 1, which is trans- N-[4-[4-amino-5-(2,3- difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]-cyclohexyl] -methanesulfonamide.

26. A compound of formula I of claim 1, which is 4-[4-amino-5-(2,3-difluoro-6- methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-sulfonic acid amide.

27. A compound of formula I of claim 1, selected from the group [4-amino-2-(4-amino-cyclohexylamino)-pyrimidin-5-yl] -(2,3-difluoro-6- methoxy-phenyl)-methanone, . : (4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3 »4- trifluoro-6-methoxy-phenyl)-methanone, : [4-amino-2-( 1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2-fluoro- 6-methoxy-phenyl)-methanone, : {4-amino-2-{1-(3-pyrrolidin-1-yl-propane-1-sulfonyl)-piperidin-4-ylamino|- pyrimidin-5-yl}-(5-fluoro-2-methoxy-phenyl)-methanone, (4-amino-2-{1-[3-(4-methyl-piperazin-1-yl)-propane- 1-sulfonyl]-piperidin-4- ylamino}-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone, [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl}-(5-fluoro- 2-methoxy-4-methyl-phenyl)-methanone, . [4-amino-2-[1-(3-chloro-propane-1 -sulfonyl) -piperidin-4-ylamino] -pyrimidin-5- : yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone, - Se Co {4-amino-2-[ 1-(3-pyrrolidin-1-yl-propane-1-sulfonl)-piperidin-4-ylamino} - : pyrimidin-5-y1}-(2,3-difluoro-6-methoxy-pheny})-methanone, oo

{4-amino-2-[1 -(3-morpholin-4-yl-propane-1-sulfonyl)-piperidin-4-ylamino] - pyrimidin-5-yl}-(2,3-difluoro-6-methoxy-phenyl)-methanone, . [4-amino-2-(1-{3-[4-(2-hydroxy-ethyl) -piperazin-1-yl]-propane-1-sulfonyl}- piperidin-4-ylaminé)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone, [4-amino-2-(1-{3-[(2-methoxy-ethyl)-methyl-amino] -propane- 1-sulfonyl}- piperidin-4-ylamino)-pyrimidin-5-yl}- (2,3-difluoro-6-methoxy-phenyl)-methanone, 1-[4-[4-amino-5-(3-methoxy-pyridine-2-carbonyl)-pyrimidin-2-ylamino]- piperidin-1-yl]-ethanone, [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(3- methoxy-pyridin-2-yl)-methanone, 1-[4-[4-amino-5-(3-methyl-thiophene-2-carbonyl)-pyrimidin-2-ylamino]- piperidin-1-yl]-ethanone, : [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(3-methyl- thiophen-2-yl)-methanone, [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-thiophen- 2-yl-methanone, [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3- difluoro-6-hydroxy-phenyl)-methanone, [4-amino-2-(azetidin-3-ylamino)-pyrimidin-5-y1]-(2,3-difluoro-6-methoxy- phenyl)-methanone, [4-amino-2-(1-methanesulfonyl-azetidin-3-ylamino)-pyrimidin-5-yl]-(2,3- difluoro-6-methoxy-phenyl)-methanone, [4-amino-2-(1-ethanesulfonyl-azetidin-3-ylamino)-pyrimidin-5-yl}-(2,3-difluoro- 6-methozy-phenyl)-methanone, and ) 25 ~ [4-amino-2-[ 1-(propane-2-sulfonyl)-azetidin-3-ylamino)] -pyrimidin-5-y}-(2,3- difluoro-6-methoxy-phenyl)-methanone. ’

28. A pharmaceutical composition comprising as an active ingredient an effective amount of a compound of any one of claims 1 to 27 and a pharmaceutically acceptable carrier or excipient. Co SE EE

-297- SE Co 29. The pharmaceutical composition of claim 28 which is suitable for parenteral administration. : : 30. The pharmaceutical composition of claim 28, wherein the compound is suitable for administration to a patient having cancer.

31. Compounds of any one of claims 1 to 27 for use as medicaments.

32. Use of compounds of any one of claims 1 to 27 for the preparation of medicaments for the treatment and control of cancer. - 33. The use of claim 32 for treating a solid breast or colon tumor.

34. A process for the preparation of a compound of formula I of claim 1, which process comprises reacting a compound of the formula (9) ! N<__-NH RY Ve ~ 2 YY | . Nx 0 rR? | : wherein R* is lower alkyl or benzyl, nis 1 or 2 and R?is as defined in claim 1, with an amine of formula . : s H,N—R In wherein R! is as defined in claim 1, to obtain a compound of the formula MH, O NT R2 PS “= Co | Hn N

; . : R CL and if desired, converting the compound of formula I into a pharmaceutically acceptable salt. BE oe BRR I

PCT/EP2004/000971

35. A compound of formula I of any one of claims 1 to 27 prepared by a process according to claim 34.

36. An intermediate compound selected from the group consisting of: 4-amino-2-methylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl- amide, 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl- amide, (4-amino-2-ethylsulfanylpyrimidin-5-yl)-(2-methoxy-phenyl)-methanone, (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)- methanone, (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)- methanone, (4-amino-2-ethanesulfonyl-pyrimidin-5-y1)-(5-fluoro-2-methoxy-phenyl)- methanone, (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)- methanone, and trans-ethanesulfonic acid (4-aminocyclohexyl)-amide, HCI Salt.

37. A substance or composition for use in a method for the treatment and control of cancer, said substance or composition comprising compounds of any one of claims 1 to 27, and said method comprising administering said substance or composition.

38. A substance or composition for use in a method of treatment of claim 37 for treating a solid breast or colon tumor.

39. A compound of any one of claims 1 to 27, 31, 35 or 36, substantially as herein described and illustrated. AMENDED SHEET

PCT/EP2004/000971 C - 299 -

40. A composition of any one of claims 28 to 30, substantially as herein described and illustrated.

41. Use of claim 32 or claim 33, substantially as herein described and illustrated.

42. A process of claim 34, substantially as herein described and illustrated.

43. A substance or composition for use in a method of treatment of claim 37 or claim 38, substantially as herein described and illustrated. 44, A new compound, a new composition, a new use of a compound of any one of claims 1 to 27, a new process for preparing a compound, or a substance or composition for a new use in a method of treatment, substantially as herein described.

45. The novel compounds, pharmaceutical compositions, processes, and uses as described herein before. AMENDED SHEET