CA2610509A1

CA2610509A1 - 1-methyl-1h-pyrazole-4-carboxamides useful as cancer chemotherapeutic agents

Info

Publication number: CA2610509A1
Application number: CA002610509A
Authority: CA
Inventors: Philip Wickens; Harold C. E. Kluender; Zhenqiu Hong; Ellalahewage Sathyajith Kumarasinghe; Charles Kreiman; Mingbao Zhang; Istvan Enyedy; Chih-Yuan Chuang
Original assignee: Individual
Current assignee: Bayer Pharma AG
Priority date: 2005-06-03
Filing date: 2006-06-02
Publication date: 2006-12-14
Also published as: WO2006133006A3; EP1891047A2; JP2008545756A; WO2006133006A2; EP1891047A4

Abstract

This invention relates to novel 1 -Methyl- lH-pyrazole-4-carboxamide compounds, pharmaceutical compositions containing such compounds, and the use of those compounds or compositions as cancer chemotherapeutic agents.

Description

1-Methyl-lH-Pyrazole-4-Carboxamides Useful as Cancer Chemotherapeutic Agents This invention relates to novel 1-Methyl-lH-pyrazole-4-carboxamide compounds, pharmaceutical compositions containing such compounds, and the use of those compounds or compositions as cancer chemotherapeutic agents.

Many disease conditions are known to be associated with deregulated angiogenesis. Among these are retinopathies; chronic inflammatory disorders including arthritis; arteriosclerosis; atherosclerosis; macular degeneration; and neoplastic diseases such as cancer. In recent years, much work has been carried out to find inhibitors of angiogenesis, in hopes of developing treatments for such disorders.

WO 2004/063330 discloses (2-carboxamido)(3-amino)thiophene compounds for the treatment of cancer.

US patent 6,448,277 (Novartis) discloses and claims certain benzamide derivatives for inhibition of VEGF receptor tyrosine kinase, tumor growth, and VEGF-dependent cell proliferation.

Published PCT application WO 02/066470 (Amgen) broadly discloses heterocycles containing amido and amino substituent groups, for prophylaxis and treatment of angiogenesis-mediated diseases. Published PCT application WO
2004/005279 (Amgen) discloses certain substituted anthranilic amide derivatives for the prophylaxis and treatment of angiogenesis-mediated diseases. Published PCT
application WO 2004/007458 (Amgen) relates to substituted 2-alkylamine nicotinic amide derivatives and their uses in treatment of cancer and other disorders.

Published PCT application WO 00/27819 (Schering) discloses certain anthranilic acid amides for treatment of diseases that are triggered by angiogenesis.
Published PCT
application WO 02/090352 (Schering) relates to selective anthranilamide pyridine amides as inhibitors of VEGFR-2 and VEGFR-3. Published PCT application WO 01/81311 (Schering) relates to substituted benzoic acid amides and use thereof for the inhibition of angiogenesis.

Anthranilamides as angiogenesis inhibitors have been discussed in a series of research papers by scientists at Novartis and Schering. See Manley, et al., J.
Med. Chem., 45, 5687-5693 (2002); Furet, et al., Bioorganic & Medicinal Chemistry Letters, 13, 2967-2971 (2003); Manley, et al., Cell. Mol. Biol. Lett., 8, 532-533 (2003); and Manley, et al., Biochimica et Biophysica Acta, 1697, 17-27 (2004).

EP-B-832 061 discloses benzamide derivatives and their use as vasopressin antagonists.

The present invention relates to a compound of Formula (I) N~ I H,Ar N NH

H IX~R
wherein Ar is selected from the group consisting of x O F
O F
F
xo F
FF
~
):D;O
F F
Ol CF3 S, CF3 and /
* ~ I O,CF3 X is CH or N;
Rl is selected from the group consisting of H, halogen, O
*-NR1-2 O
*AN ~R1-4 *-N~R1-5 and O

*_N N, wherein R1-2 is selected from the group consisting of = H, = (C1-C4)alkoxy, = (Cl-C4)alkyl, wherein said (Cl-C4)alkyl can be substituted with 0, 1, or 2 groups independently selected from - hydroxy, - (C1-C4)alkylamino, - (Cl-C4)acyloxy, - (C1-C4)alkoxy, and -(Ca-C4)alkoxy substituted with 0,1 or 2(Cl-C4)alkoxy groups, - wherein said (Cl-C4)alkyl is independently optionally substituted with F up to the perfluoro level, = 5- or 6-membered heteroaryl, or = phenyl substituted with 0, 1, or 2 groups independently selected from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano;
R1"3 is H or (C1-C4)alkyl;
Rl"4, R1-5 and R1"6 are independently selected from the group consisting of = H, = indan-5-yl, = phenyl substituted with 0, 1, or 2 groups independently selected from (C1-C4)alkyl, halo, nitro, (Cl-C4)alkoxy and cyano, = 5- or 6-membered heteroaryl substituted with 0,1 or 2 groups selected from - cyano, - halo, - nitro, - (Cl-C4)alkyl, wherein said (Cl-C4)alkyl is optionally substituted with 0, 1, or 2 groups selected from (Cl-Qalkylamino, (C1-C4)acyloxy, (Cl-C4)alkoxy, and (C2-C4)alkoxy substituted with up to 0, 1 or 2(Cl-C4)alkoxy groups, = (C3-C6)cycloalkyl substituted with 0,1 or 2 groups selected from (C1-C4)alkyl, (C1-C4)alkoxy, cyano, and halo, and = (C1-C6)alkyl, wherein said (Cl-C6)alkyl is independently substituted with 0 or 1 group selected from - NH2, - (C1-C4)alkoxy, - (C2-C4)alkoxy independently substituted with 0,1, 2 or 3(Cl-C4)alkoxy and OH groups, and independently optionally substituted with fluorine up to the perfluoro level, - carboxyl, - (Cl-C4)alkoxycarbonyl - (CI-C4)alkylamino, - aminocarbonyl, - (C1-C4)alkylsulfonyl, - phenyl substituted with 0, 1, or 2 groups independently selected from (C1-C4)alkyl, halo, nitro, (Cl-C4)alkoxy and cyano, - 5- or 6-membered heteroaryl independently substituted with 0, 1, 2 or 3 groups selected from (C1-C4)alkyl, (Cl-C4)alkoxy, cyano, halo, and nitro and - heterocyclyl independently substituted with 0, 1, 2 or 3 groups selected from (C1-C4)a1ky1, (C1-C4)alkoxy, cyano, and halo, - and wherein said (Cl-C6)alkyl is independently substituted with 0, 1 or 2 OH or halo groups, - and wherein said (C1-C6)alkyl is independently optionally substituted with F up to the perfluoro level;
and R1"3 and Rl-4, Rl"3 and R1-5 , and R1"3 and Rl"6 , when attached to the same nitrogen atom, may form, together with the N atom to which they are attached, a 5- or 6-membered saturated heterocyclic ring selected from pyrrolidinyl, morpholinyl, thiomorpholinyl and piperizinyl optionally substituted on N with (Cl-C4)alkyl;

or a pharmaceutically acceptable salt thereof.

The invention also relates to pharmaceutical compositions which comprise a compound of Formula (I) as defined above plus a pharmaceutically acceptable carrier.
In addition, the invention relates to a method of treating cancer coinprising administering to a subject in need thereof an effective amount of a compound of Formula (I) as defined above.

Pharmaceutically acceptable salts of the compounds (1) include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

Pharmaceutically acceptable salts of the compounds (1) also include salts of customary bases, such as for example and preferably alkali metal salts (for example sodium and potassium salts, alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as illustratively and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, arginine, lysine, ethylenediamine and methylpiperidine.

Solvates for the puiposes of the invention are those forms of the compounds that coordinate with solvent molecules to form a complex in the solid or liquid state. Hydrates are a specific form of solvates, where the coordination is with water.

For the purposes of the present invention, the substituents have the following meanings, unless otherwise specified:

The terms "halogen" and "halo" mean Cl, Br, F and I, where Cl, Br and F are preferred.

The terms "(C1-C4)alkyl" and "(C1-C6)alkyl" mean a linear or branched saturated carbon group having from about 1 to about 4 C atoms or from about 1 to about 6 C atoms, respectively. Such groups include but are not limited to methyl, ethyl, n-propyl, isopropyl, n, butyl, isobutyl, sec-butyl, tert-butyl, and the like.

The term "(C3-C6)cycloalkyl" means a saturated carbocyclic ring group having from about 3 to about 6 C atoms. Such groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term "(Cl-C4)alkoxy" means a linear or branched saturated carbon group having from about 1 to about 4 C atoms, said carbon group being attached to an 0 atom.
The 0 atom is the point of attachment of the alkoxy substituent to the rest of the molecule.
Such groups include but are not limited to methoxy, ethoxy, n-propoxy, isopropoxy, and the like.

The term "(Cl-C4)alkylamino" means an amino group having from one or two (independently selected) (Cl-C4)alkyl substituents, illustratively representing methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylaniino, N-methyl-N-n-propylamino, N-isopropyl-N n-propylamino, N-t-butyl-N-methylamino, N-ethyl-N-n-pentylamino, N-n-hexyl N-methylamino and the like.

The term "(C1-C4)alkylsulfonyl" means a sulfonyl group having a(C1-C4)alkyl substituent, illustratively representing methylsulfonyl, ethyl sulfonyl, isopropylsulfonyl, t-butylsulfonyl, and the like.

The term "(Cl-C4)alkoxycarbonyl" means a(C1-C4)alkoxygroup bound to the C
atom of a carbonyl group[ -C(O) - ]said group being bound to the rest of the molecule, illustratively representing methoxycarbonyl, ethoxycarbonyl, fz-propoxycarbonyol, i-propoxycarbonyl, t-butoxycarbonyl, and the like The term "(Cl-C4)acyloxy" means a(Cl-C4)group bound to the C atom of a carboxyl group [-C(O)O- ], said group being bound by the oxygen atom to the rest of the molecule illustratively representing formyloxy, acetyloxy (acetoxy), propanoyloxy, butanoyloxy, t-butanoyloxy and the like The term "5- or 6-membered heteroaryl" means, respectively, (1) an aromatic ring made of 5 atoms and having 1, 2, 3 or 4 heteroatom(s) each selected independently from 0, N, and S, the rest being C atoms, with the proviso that there can be no more than 10 or S atom in the heteroaryl. This heteroaryl is attached to the core molecule at any available C or N atom and is optionally substituted at any available C or N atom with the recited substituents. Such groups include pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, oxadiazole, thiadiazole, and tetrazole in all their possible isomeric forms;
or (2) an aromatic ring made of 6 atoms, 1, 2, or 3 of which are N atoms, the rest being C, where the heterocycle is attached to the core molecule at any available C atom and is optionally substituted at any available C atom with the recited substituents.
Such groups include pyridine, pyrimidine, pyridazine and triazine in all their possible isomeric forms.

The term "heterocyclyl" means a 5-or 6- membered saturated or partially saturated heterocyclic ring containing 1-2 heteroatoms selected from 0, S or N, the remaining atoms being made up of C atoms, with the proviso that when there are 2 0 atoms they must be nonadjacent. This heterocycle is attached to the core molecule at any available C or N
atom and is optionally substituted at any available C or N atom with the recited substituents. Such groups include pyrrolidine, tetrahydrofuryl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyrano, piperizinyl, imidazolinyl, pyrazolinyl, morpholinyl, thiomorpholinyl and the like in all their possible isomeric forms.

A * symbol next to a bond denotes the point of attachment in the molecule.

The compounds of this invention may contain one or more asymmetric centers, depending upon the location and nature of the various substituents desired.
Asymmetric carbon atoms may be present in the (R) or (S) configuration. It is intended that all possible stereoisomers (including enantiomers and diastereomers) are included within the scope of the present invention. Preferred compounds are those with the absolute configuration of the compound of this invention which exhibits the more desirable biological activity.
Separated, pure or partially purified stereoisomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention.
The purification of said isomers and the separation of said stereoisomeric mixtures can be accomplished by standard techniques known in the art.

In another embodiment, the invention relates to a compound of Formula (I), wherein Ar is selected from the group consisting of x p F

F
F
O F F
O
F F

/ I o'CF3 , S, CF3 and /

* ~ I O'CF3 X is CH or N;

Rl is selected from the group consisting of O
*-N'k R1-2 O

* N

*-N iR1-5 and O

wherein R1-2 is selected from the group consisting of = (Cl-C4)alkyl, wherein said (Cl-C4)alkyl is substituted with 1 or 2 groups independently selected from - hydroxy, - (C1-C4)alkylamino, - (Cl-C4)acyloxy, - (Cl-C4)alkoxy, and - (C2-C4)alkoxy substituted with 0,1 or 2(C1-C4)alkoxy groups, - wherein said (C1-C4)alkyl is independently optionally substituted with F up to the perfluoro level, = 5- or 6-membered heteroaryl, or = phenyl substituted with 1 or 2 groups independently selected from (Cl-C4)alkyl, halo, nitro, (Cl-C4)alkoxy and cyano;
R1"3 is H or (Cl-C4)alkyl;
R1-4 and R1-5 are independently selected from the group consisting of = indan-5-yl, = phenyl substituted with 1 or 2 groups independently selected from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano, = 5- or 6-membered heteroaryl substituted with 1 or 2 groups selected from - cyano, - halo, - nitro, - (Cl-C4)alkyl, wherein said (Cl-C4)alkyl is optionally substituted with 0, 1, or 2 groups selected from (C1-C4)alkylamino, (C1-C4)acyloxy, (Cl-C4)alkoxy, and (C2-C4)alkoxy substituted with up to 0, 1 or 2(Cr-C4)alkoxy groups, =(C3-C6)cycloalkyl substituted with 1 or 2 groups selected from (Cl-C4)alkyl, (C1-C4)alkoxy, cyano, and halo, and = (Cl-C6)alkyl, wherein said (C1-C6)alkyl is independently substituted with 1 group selected from - NH2, - (C1-C4)alkoxy, - (C2-C4)alkoxy independently substituted with 0,1, 2 or 3(Cl-C4)alkoxy and OH groups, and independently optionally substituted with fluorine up to the perfluoro level, - carboxyl, - (Cl-C4)alkoxycarbonyl - (Cl-C4)alkylamino, - aminocarbonyl, - (Cl-C4)alkylsulfonyl, - phenyl substituted with 0, 1, or 2 groups independently selected from (C1-C4)alkyl, halo, nitro, (Cl-C4)alkoxy and cyano, - 5- or 6-membered heteroaryl independently substituted with 0, 1, 2 or 3 groups selected from (C1-C4)alkyl, (C1-C4)alkoxy, cyano, halo, and nitro and - heterocyclyl independently substituted with 0, 1, 2 or 3 groups selected from (C1-C4)alkyl, (Cl-C4)alkoxy, cyano, and halo, - and wherein said (Cl-C6)alkyl is independently substituted with 0, 1 or 2 OH or halo groups, - and wherein said (Cl-C6)alkyl is independently optionally substituted with F up to the perfluoro level;
R1"6 is selected from the group consisting of = H

= indan-5-yl, = phenyl substituted with 0, 1, or 2 groups independently selected from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano, = 5- or 6-membered heteroaryl substituted with 0,1 or 2 groups selected from - cyano, - halo, - nitro, - (Cl-C4)alkyl, wherein said (Cl-C4)alkyl is optionally substituted with 0, 1, or 2 groups selected from (C1-C4)alkylamino, (Cl-C4)acyloxy, (C1-C4)alkoxy, and (C2-C4)alkoxy substituted with up to 0, 1 or 2(C1-C4)alkoxy groups, = (C3-C6)cycloalkyl substituted with 0,1 or 2 groups selected from (C1-C4)alkyl, (Cl-C4)alkoxy, cyano, and halo, and = (C1-C6)alkyl, wherein said (Cl-C6)alkyl is independently substituted with 0 or 1 group selected from - NH2, - (Cl-C4)alkoxy, - (C2-C4)alkoxy independently substituted with 0,1, 2 or 3(C1-C4)alkoxy and OH groups, and independently optionally substituted with fluorine up to the perfluoro level, - carboxyl, - (C1-C4)alkoxycarbonyl - (C1-C4)alkylamino, - aininocarbonyl, - (C1-C4)alkylsulfonyl, - phenyl substituted with 0, 1, or 2 groups independently selected from (Cl-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano, - 5- or 6-membered heteroaryl independently substituted with 0, 1, 2 or 3 groups selected from (C1-C4)alkyl, (C1-C4)alkoxy, cyano, halo, and nitro and - heterocyclyl independently substituted with 0, 1, 2 or 3 groups selected from (Cl-C4)alkyl, (Cl-C4)alkoxy, cyano, and halo, - and wherein said (C1-C6)alkyl is independently substituted with 0, 1 or 2 OH or halo groups, - and wherein said (C1-C6)alkyl is independently optionally substituted with F up to the perfluoro level;
and Rl 3 and Rl"4, Rl_3 and R1-5, and R1-3 and Rl 6, when attached to the same nitrogen atom, may form, together with the N atom to which they are attached, a 5- or 6-membered saturated heterocyclic ring selected from pyrrolidinyl, morpholinyl, thiomorpholinyl and piperizinyl optionally substituted on N with (Cl-C4)alkyl;

or a pharmaceutically acceptable salt thereof.

In another einbodiment, the invention relates to a compound of Formula (I), wherein Ar is selected from the group consisting of OcX

~ F
/ O F
~
F
o-f F F
O
F F

Ol CF3 and S, CF3 *~ =
X is CH;
Rl is selected from the group consisting of * R1-5 and O

*_N N, wherein R1-3 is H or (C1-C4)alkyl, R1-5 is selected from the group consisting of indan-5-yl, phenyl substituted with 1 or 2 groups independently selected from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano, 5- or 6-membered heteroaryl substituted with 1 or 2 groups selected from cyano, halo, nitro, (C1-C4)alkyl, wherein said (Cl-C4)alkyl is optionally substituted with 0, 1, or 2 groups selected from (Cl-C4)alkylamino, (C1-C4)acyloxy, (C1-C4)alkoxy, and (C2-C4)alkoxy substituted with up to 0, 1 or 2(C1-C4)alkoxy groups;
(C3-C6)cycloalkyl substituted with 1 or 2 groups selected from (Cl-C4)alkyl, (C1-C4)alkoxy, cyano, and halo;

and (Cl-C6)alkyl, wherein said (C1-C6)alkyl is independently substituted with lgroup selected from NH2, (Cl-C4)alkoxy, (C2-C4)alkoxy independently substituted with 0,1, 2 or 3(C1-C4)alkoxy and OH groups, and independently optionally substituted with fluorine up to the perfluoro level, carboxyl, (C 1-C4) alkoxycarbonyl (Cl-C4)alkylamino, aminocarbonyl, (Cl-C4)alkylsulfonyl, phenyl substituted with 0, 1, or 2 groups independently selected from (Cl-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano, 5- or 6-membered heteroaryl independently substituted with 0, 1, 2 or 3 groups selected from (Cl-C4)a1ky1, (Cl-C4)alkoxy, cyano, halo, and nitro and heterocyclyl is independently substituted with 0, 1, 2 or 3 groups selected from (Cl-C4)alkyl, (C1-C4)alkoxy, cyano, and halo, and wherein said (C1-C6)alkyl is independently substituted with 0, 1 or 2 OH or halo groups, and wherein said (C1-C6)alkyl is independently optionally substituted with F up to the perfluoro level;
Ri-6 is selected from the group consisting of H, indan-5-yl, phenyl substituted with 0, 1, or 2 groups independently selected from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano, 5- or 6-membered heteroaryl substituted with 0, 1 or 2 groups selected from cyano, halo, nitro, (C1-C4)alkyl, wherein said (C1-C4)alkyl is optionally substituted with 0, 1, or 2 groups selected from (Cl-C4)alkylamino, (C1-C4)acyloxy, (C1-C4)alkoxy, and (C2-C4)alkoxy substituted with up to 0, 1 or 2(Cl-C4)alkoxy groups;
(C3-C6)cycloalkyl substituted with 0,1 or 2 groups selected from (Cl-C4)alkyl, (Cl-C4)alkoxy, cyano, and halo;
and (Ci-C6)alkyl, wherein said (Cl-C6)alkyl is independently substituted with 0 or 1 group selected from NH2, (C1-C4)alkoxy, (C2-C4)alkoxy independently substituted with 0,1, 2 or 3(Cl-C4)alkoxy and OH groups, and independently optionally substituted with fluorine up to the perfluoro level, carboxyl, (C 1-C4)alkoxycarbonyl (Cl-C4)alkylamino, aminocarbonyl, (Cl-C~)alkylsulfonyl, phenyl substituted with 0, 1, or 2 groups independently selected from (Cl-C4)alkyl, halo, nitro, (Cl-C4)alkoxy and cyano, 5- or 6-membered heteroaryl independently substituted with 0, 1, 2 or 3 groups selected from (Cl-C4)alkyl, (Cl-C4)alkoxy, cyano, halo, and nitro and heterocyclyl is independently substituted with 0, 1, 2 or 3 groups selected from (C1-C4)alkyl, (Cl-C4)alkoxy, cyano, and halo, and wherein said (C1-C6)alkyl is independently substituted with 0, 1 or 2 OH or halo groups, and wherein said (Cl-C6)alkyl is independently optionally substituted with F up to the perfluoro level;
and R1-3 and R1-5, and Rl 3 and R1"6, when attached to the same nitrogen atom, may form, together with the N atom to which they are attached, a 5-or 6-membered saturated heterocyclic ring selected from pyrrolidinyl, morpholinyl, thiomorpholinyl and piperizinyl optionally substituted on N with (Cl-C4)alkyl;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention relates to a compound of Formula (I) Ar is selected from the group consisting of F

iaoT O F
F
F

F F
/ IOt * \ O

F F
O, CF3 and S, CF3 *~ .
X is CH;
Rl is selected from the group consisting of *_N"IR1-5 and O

*_N N>

wherein R1-3 is H, R1-5 is (C1-C6)alkyl, wherein said (C1-C6)alkyl is independently substituted with 1 group selected from (Cl-C4)alkoxy, (C2-C4)alkoxy independently substituted with 0,1, or 2(C1-C4)alkoxy and OH groups, and independently optionally substituted with fluorine up to the perfluoro level, and wherein said (C1-C6)alkyl is independently substituted with 0, 1 or 2 OH or halo groups, and wherein said (C1-C6)alkyl is independently optionally substituted with F up to the perfluoro level;
R1-6 is selected from the group H, and (C1-C6)alkyl, wherein said (Cl-C6)alkyl is independently substituted with 0 or 1 group selected from (Cl-C4)alkoxy, (C2-C4)alkoxy independently substituted with 0,1, 2 or 3(Cl-C4)alkoxy and OH groups, and independently optionally substituted with fluorine up to the perfluoro level, and wherein said (C1-C6)alkyl is independently substituted with 0, 1 or 2 OH or halo groups, and wherein said (Cl-C6)alkyl is independently optionally substituted with F up to the perfluoro level;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention relates to a compound of Formula (I) Ar is selected from the group consisting of ::) CO xF

/ O F
* ~ I F
O
F

O F F F

Ol CF3 and Z1;t1F3.
X is CH;
Rl is selected from the group consisting of O

*_N N.

wherein R1-3 is H, R1-6 is selected from the group H, and (Ci-C6)alkyl, wherein said (C1-C6)alkyl is independently substituted with 0 or 1 group selected from (C1-C4)alkoxy, (C2-C4)alkoxy independently substituted with 0,1, 2 or 3(C1-C4)alkoxy and OH groups, and independently optionally substituted with fluorine up to the perfluoro level, and wherein said (C1-C6)alkyl is independently substituted with 0, 1 or 2 OH or halo groups, and wherein said (Cl-C6)alkyl is independently optionally substituted with F up to the perfluoro level;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention relates to a process for making a compound of formula (I), comprising (A) reacting, with or without first hydrolizing the ester group -COOR', a compound of formula (VI) O

ORI
N NH

Y, Y
N (VI) wherein X and Rl have the meaning described above, and R' is lower alkyl, with a compound of formula Ar-NH2 (VIII), wherein Ar has the meaning described above, for example in the presence of a coupling agent such as PyBOP; or (B) reacting a compound of formula (IX) O
N~ I H,Ar H3C (IX) wherein Ar has the meaning described above, with a compound of formula (IV) CHO

X
N~R1 (IV), wherein X and Rl have the meaning described above, and subsequently reducing the resulting compound; or (C) reacting a compound of formula (IX), wherein Ar has the meaning described above, with a compound of formula (V) CH2Ig X
N~Rl (V), wherein lg represents a leaving group, such as halo, OTs or OMs; or (D) reacting a compound of formula (IIa) O
N//X OR' N N O

X
~-R1 _ N (Ra) wherein X and Rl have the meaning described above, and R' is lower alkyl, with a compound of formula (VIII) ArNH2 (VIII), wherein Ar has the meaning described above, in the presence of (R')3A1, wherein R' is lower alkyl, or (E) first hydrolizing the ester group -COOR' of a compound of formula (IIa) as described above, and subsequently reacting the resulting compound with a compound of formula (VIII) as described above, for example in the presence of a coupling agent such as PyBOP.

General Methods of Preparation Compounds of Formula (I) may be prepared by synthetic procedures known to those skilled in the art or by methods analogous thereto. These methods are summarized below in Reaction Scheme 1.

Unless otherwise specifically defined, Rl and X have the same meanings as defined hereinabove.

Reaction Scheme 1 N~ ~ OR' NH2 (BOC)20 Ni I OR' H3C base N N(BOC)õ

(III) R' = lower alkyl (VII) n=1 or 2 CHO

1 I~ X ArNH2 (VI II), (R')3AI
~ Ar-NH2 or N R1 (VIII) (IV) 1) hydrolysis (R')3AI 2) ArNH2 (VIII), 2. reduction coupling agent, e.g., or PyBOP
Ig = leaving group, 3) TFA
CH21g e.g., halo, OTs or OMs 0 I X
N~R1 N I H,Ar (V) H H2 0 3C N (IX) Ni I OR
N NH CHO
H3C CH2 X R1 1. X
~ N~R1 (VI) (IV) 2. reduction Ar-NH2 or (VIII), (R')3AI CH21g or hydrolysis, 0 N~R1 Ar-NH2 (V) (VIII) Ni H.Ar coupling agent, ~N
e.g., PyBOP NH

H),T X

H

(I) As illustrated in Reaction Scheme 1, two general synthetic routes can be used to prepare the compounds of Formula (I).
In one route, the amino group of the compound of Formula (III), is subjected to either reductive amination using a pyridine or pyrimidine carboxaldehyde of Formula (IV) and a reducing agent, such as sodium triacetoxyborohydride, or to direct N-alkylation using a pyridine or pyrimidine methyl halide, tosylate or mesylate of Formula (V) and a optional base such as pyridine or K2C03, or a catalyst such as sodium iodide.
The product formed, Formula (VI), is then allowed to react with an aromatic amine of Formula (VIII) in the presence of a coupling agent such as (R')3A1(where R' = lower alkyl) giving the compound of Formula (I), or alternatively, the ester of Formula (VI) is hydrolyzed to the acid which is then coupled to the amine (VIII) using a coupling agent such as PyBOP.
In the second route, the compound of Formula (III) is converted to the aminoamide of Formula (IX) either directly by reaction with an aromatic amine of Formula (VIII) as described above, or by first protecting the amino function, e.g., as a BOC
derivative (VII), and subsequent coupling with (VIII), either directly with (R')3A1, or via hydrolysis, and then coupling in the presence of PyBOP, followed by deprotection. The Formula (IX) compound is then converted to the Formula (I) compound using either the reductive amination method or direct N-alkylation as described above for preparation of (VI).
An additional route shown below in Scheme la is also possible. The amino group of the compound of formula (III) can be acylated using an acylating agent such as acetic anhydride and formic acid. N-alkylation of the acylated product Formula (II) using a pyridine or pyrimidine methyl halide, tosylate or mesylate of Formula (V) and a base such as DBU or K2CO3. The product formed, Formula (IIa), is then allowed to react with an aromatic amine of Formula (VIII) in the presence of a coupling agent such as (R')3Al (where R' = lower alkyl) giving the compound of Formula (I) after a basic work up, or alternatively, the ester of Formula (IIa) is hydrolyzed to the acid in which the N-formyl group is also removed which is then coupled to the amine (VIII) using a coupling agent such as PyBOP.

Reaction Scheme la (RCO)20 OR Base Ni I OR' NH2 or N NH R
H3C RCOCI H3C ~ Base (III) (II) O CH21g I~ X Ig = leaving group, '= lower alkyl R
e.g., halo, OT
R1 or OMs (V) O
N~ OR' ~N O
, x -N
(Ila) ZorArNH2 ~ ~~R1 VIII), (R')3AI
O 1) Hydr olysis & PG removal (OH-) Ar 2) ArNH2 (VIII), N s N' H coupling agent, e.g., N NH PyBOP

H ),,IX
H I
(I) Starting materials of Formulae (III), (IV), (V) and (VIII) are commercially available (e.g., Lanxess, Germany) or may be prepared by standard means well known in the art, or as described in Reaction Schemes 2-8.
Reaction Scheme 2 X CIxRi-2 N NH2 N" NR1_2 (X) (Va) Compounds of Formula (Va), O
*-Nj~ R1-2 [Formula (V) where Rl is H and lg is Cl], may be prepared as shown in Reaction Scheme 2 by reaction of an acid chloride with a chloromethyl heteroarylaniine of Formula (X), generally in the presence of a base such as triethylamine.

Reaction Scheme 3 OH Opg Opg %~ X R~19 ~

(XI) (XII) (XIII) Opg OH Ig X X X
-- _~
I N~NH
N~NBOC N~NH
(XIV) R 1-5 1 5 R1-5 l (XV) R (Vb) pg = protecting group, e.g., BOC

Ig = leaving group, e.g., halo, MsO, etc.

Compounds of Formula (Vb) [Formula (V) where R' is H ], can be prepared as shown in Reaction Scheme 3 from hydoxymethylheteroaryl amines of Formula (XI). Protection of the alcohol and conversion to the BOC-derivative of Formula (XIII) is followed by N-alkylation to give the intermediate of Formula (XIV).
Deprotection of the alcohol and amine, followed by conversion of the hydroxy group to a leaving group, (for example, using SOC12, when lg is Cl) gives the intermediate of Formula (Vb).

Reaction Scheme 4 O OR' OH

X LiBH4 X (R1-3)(R1-5)NH
N" CI N CI
(XVI) (XVII) OH ig X
-~ I X
NNR1-3R1-5 N111, NRi-3R1-5 (XVIII) (Vc) R' = lower alkyl Ig = leaving group, e.g., halo, MsO
Ri-5 *

Compounds of Formula (Vc) [Formula (V) where Rl is 1R1-3 ] can be prepared by the route illustrated in Reaction Scheme 4. The chloroheteroarylcarboxylic acid derivative of Formula (XVI) is reduced to the chloroheteroaryl alcohol of Formula (XVII) with a standard reagent such as lithium borohydride. Reaction of the chloro compound with an amine of Formula (Rl-3)(R1-s)NH gives the intermediate alcohol of Formula (XVIlI). Conversion of this alcohol to a leaving group, e.g. mesylate, completes the synthesis of the compound of Formula (Vc) Reaction Scheme 5 O OH O OH O OH
X H+ X NH4OAc X
~
NO R'OH N-~YO NH4CI N~O
OH OR' NH2 (XIX) (XX) (XXI) O OMe OH Ig Mel X NaBH4 X Ig-halo X
~ I I N O base N O
Na2CO3 N~ O

(XXII) (XXIII) (Vd) Compounds of Formula (Vd) [Formula (V) where Rl is *A NH2], can be prepared as shown in Reaction Scheme 5 from the dicarboxylic acid of Formula (XIX) by conversion through the half acid ester (XX) to the acid amide of Formula (XXI).
Esterification of (XXI) provides (XXII) which can be reduced with sodium borohydride to the alcohol (XXIII) and then converted to the Formula (Vd) compound, using for example MsCI and a base such as triethylamine.

Reaction Scheme 6 0 OEt O OEt N N- O

(XXIV) (XXII) An alternate method of preparing the pyridine amide ester of Formula (XXII) is via the Minisci reaction shown in Reaction Scheme 6 in which the pyridine carboxylic acid ester is stirred in formamide with cooling to 10 C in the presence of an equivalent of concentrated H2SO4, FeSO4 and H,,02.

Reaction Scheme 8 CI CI
I x R1-6NC0 X O

N NH or N N~N~R1-6 (X) (Vf) O

Compounds of Formula (Vf) [Formula (V) where Rl is R1 3 R1-3 ] can be prepared by the route shown in Reaction Scheme 8. In the case that the R1-3 on the right is H, the intermediate of Formula (X) is allowed to react with an isocyanate of Formula R1-6NC0 in an aprotic solvent such as dichloromethane. In the case that the R1-3 on the right is alkyl, or that R1-3 and R1-6 are combined in a cyclic structure, the intermediate of Formula (X) is allowed to react with a carbamoyl chloride Formula R1-6 R1-3NCOC1 in an aprotic solvent such as dichloromethane in the presence of a base such as triethylamine or potassium carbonate. The use of a starting material of Formula (X) in which the R1-3 on the left is O

*_N N, alkyl results in the preparation of a urea of structure (Vf) where Rl is R1 3 R1-3 in which the R1-3 group on the left is alkyl.
In the cases that the isocyanate of Formula R1-6NC0 is not commercially available (and R1"3 is H on the right side), it can conveniently be prepared by treatment of the amine of Formula R1"6NH2, wherein Rl"6 is aryl or heteroaryl, with phosgene, diphosgene or triphosgene in a suitable solvent such as ethyl acetate. When R1-6 is alkyl or substituted alkyl, the preferred method is to treat the corresponding alkyl halide or dialkyl sulfate with inorganic cyanates. These methods, as well as others, are well known to those skilled in the art and examples are described in S. R. Sandler and W. Karo "Organic Functional Group Preparations," vol 12, 2"d ed., p 364-375, 1983, Academic Press and references cited therein.
In the cases that the carbamoyl chloride of Formula Rl"6 Rl-3NCOC1 is not commercially available, it can conveniently be prepared by treatment of the amine of Formula Rl"6 Rl"3NH with phosgene, diphosgene or triphosgene in a suitable solvent such as dichloromethane at 0-4 C. Optionally, the N-benzyl protected amine of Formula Rl"6 R1"3NCH2(C5H6) can be reacted with triphosgene as described by M.G. Banwell, et al, J.
Org. Cheni. 2003, 68, 613-616.

A variety of compounds of Formula (I) can be prepared by elaboration of compounds, also of Formula (I), prepared by the above schemes. These elaboration methods are illustrated below in Reaction Schemes 10-13.

Reaction Scheme 10 O
Ns I H'Ar N NH

NN ~
~
NH2OH (Ij) H3C

O O
N, H'Ar O H'Ar N NH CI11~ R1-2 N NH

O

N" NH2 N" 'N R
H
(Ia) (Ib) ~IS-Ria H'Ar N N,Ar H
H C NH HCN NH
3 g X X
~ 0 I 0 N N'SR1 7 NNN,R1 6 (Ic) H (Id) H H

For example, the dimethyl pyrrole compound of Formula (Ij) is made by coupling [2-(2,5-dimethyl-lH-pyrrol-1-yl)pyridin-4-yl]methyl methanesulfonate with 5-amino-N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-lH-pyrazole-4-carboxamide as shown in Scheme 1. [2-(2,5-dimethyl-IH-pyrrol-1-yl)pyridin-4-yl]methyl methanesulfonate is made by coupling (2-aminopyridin-4-yl)methanol with hexane-2,5-dione using catalytic acid and then mesylation of the alcohol produced. The dimethyl pyrrole compound of Formula (Ij), can be deprotected to give a compound of Formula (Ia).

The amine can then be converted to the amide compound of Formula (Ib), the sulfonamide of Formula (Ic) or the urea of Formula (Id) as shown in Reaction Scheme 10, by reaction with an acid chloride, sulfonyl chloride or isocyanate, respectively.

Reaction Scheme 11 O O
,Ar N
11 N,Ar 200 OC 0:1 N I H Pyridine N H
' N sealed tube N N

\X (R1-3)(R1-5)NH X
I I
i5 R
NCI N ' I
(le) Ri 3 (If) Additionally, the chloro compound of Formula (Ie) can be converted to the substituted amino compound of Formula (If) by reaction with an amine and a base such as pyridine in a sealed tube at elevated temperatures.

Reaction Scheme 12 O
O
N N.Ar Ar ,N N~ I HAr I H
'N
NH
HsC H3C NH R1-4R1-aNH H3C HN
X DMF-DMA

N~ ~ O N
N
NH

(19) (Ih) (I~) Esters of Formula (Ih) and substituted amides of Formula (Ii) may be prepared from the unsubstituted amide of Formula (Ig) by the sequence illustrated in Reaction Scheme 12. Reaction of the amide (Ig) with dimethylformamide-dimethylacetal (DMF-DMA) in methanol provides the ester of Formula (Ih); reaction of the ester with a substituted amine gives the amide of Formula (Ii).

Generally, a desired salt of a compound of this invention can be prepared in situ during the final isolation and purification of a compound by means well known in the art.
Or, a desired salt can be prepared by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
These methods are conventional and would be readily apparent to one skilled in the art.
Additionally, sensitive or reactive groups on the compound of this invention may need to be protected and deprotected during any of the above methods.
Protecting groups in general may be added and removed by conventional methods well known in the art (see, for example, T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis;
Wiley: New York, (1999).

By using the general schemes illustrated above and choosing the appropriate starting materials the compounds of the invention may be prepared. To further illustrate the invention, the following specific examples are provided, but are not meant to limit the scope of the invention in any way.

A. Examples Abbreviations and Acronyms When the following abbreviations are used throughout the disclosure, they have the following meaning:
bm broad multiplet BOC t-butoxycarbonyl bp boiling point bs broad singlet bt broad triplet CD3CN acetonitrile-d3 CD3OD methanol-d4 Celite0 registered trademark of Celite Corp. brand of diatomaceous earth d doublet DMSO-d6 dimethylsulfoxide-d6 DMF N,N dimethylformamide EtOAc ethyl acetate h hour(s) 1H NMR proton nuclear magnetic resonance HPLC high performance liquid chromatography LCMS liquid chromatography / mass spectroscopy .min minute(s) ML inilliliter(s) Ms methanesulfonyl nilz mass to charge ratio PyBOP benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate rt room temperature RT retention time (HPLC or LCMS) s singlet t triplet TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography Ts p-toluenesulfonyl General Analytical Procedures The stiucture of representative compounds of this invention were confirmed using the following procedures.

Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Hewlett Packard 5890 Gas Chromatograph with a J & W DB-5 column (0.25 M coating; 30 m x 0.25 mm). The ion source is maintained at 250 C and spectra were scanned from 50-800 amu at 2 sec per scan.
High pressure liquid chromatography-electrospray mass spectra (LC-MS) were obtained using either a:

(A) Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2 x 23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-1200 amu using a variable ion time according to the number of ions in the source. The eluents were A: 2% acetonitrile in water with 0.02% TFA and B:
2%
water in acetonitrile with 0.018% TFA. Gradient elution from 10% B to 95% over 3.5 min at a flowrate of 1.0 mL/min is used with an initial hold of 0.5 min and a final hold at 95%
B of 0.5 min. Total run time is 6.5 min.
or (B) Gilson HPLC system equipped with two Gilson 306 pumps, a Gilson 215 Autosampler, a Gilson diode array detector, a YMC Pro C-18 column (2 x 23 mm, 120 A), and a Micromass LCZ single quadrupole mass spectrometer with z-spray electrospray ionization. Spectra were scanned from 120-800 amu over 1.5 seconds. ELSD
(Evaporative Light Scattering Detector) data is also acquired as an analog channel. The eluents were A: 2% acetonitrile in water with 0.02% TFA and B: 2% water in acetonitrile with 0.018% TFA. Gradient elution from 10% B to 90% over 3.5 min at a flowrate of 1.5 mL/min is used with an initial hold of 0.5 rnin and a final hold at 90% B of 0.5 nzin. Total run time is 4.8 min. An extra switching valve is used for colun-m switching and regeneration.

Routine one-dimensional NMR spectroscopy is performed on 400 MHz Varian Mercury-plus spectrometers. The samples were dissolved in deuterated solvents obtained from Cambridge Isotope Labs, and transferred to 5 mm ID Wilmad NMR tubes. The spectra were acquired at 293 K. The chemical shifts were recorded on the ppm scale and were referenced to the appropriate solvent signals, such as 2.49 ppm for DMSO-d6, 1.93 ppm for CD3CN, 3.30 ppm for CD3OD 5.32 ppm for CD2C12 and 7.26 ppm for CDC13 for 1H spectra.

Preparation of Intermediates Intermediate A
Preparation of 5-amino-N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-lH-pyrazole-4-carboxamide O XF
N~ ~ H O

Step 1: Preparation of ethyl 5-fbis(tert-butoxycarbonyl)aminol-l-methyl-lH-pyrazole-4-carboxylate ~-CH3 N/ I oC CH

~G~3 H3C O~ C CH

Ethyl 5-amino-l-methyl-lH-pyrazole-4-carboxylate (4.7 g, 27.78) in dichloromethane (100 mL) was stirred under nitrogen in a 500 mL flask as di-tert-butyl dicarbonate (7.88 g, 36.11 mmol) was added followed by N,N-dimethylpyridin-4-amine (339 mg, 2.78 mmol). The solution was stirred for 16 h. An additonal 5 g of di-tert-butyl dicarbonate was added and the solution was stirred for an additional 2 h. Very little starting material remained at this point and the solvents were evaporated to give a residue that was purified using silica gel. Products were eluted with a gradient from 0-80 % ethyl acetate in hexane to yield 8.1 g (79%) of the title pure material.
1H NMR (300 MHz, CD2C12-d2) 8 7.85 (s, 1H), 4.25 (q, 2H), 2.68 (s, 3H), 1.40 (s, 18H), 1.30 (t, 3H); ES-MS nilz 370.0 [M+H]+, LCMS RT (min) 3.17.

Step 2: Preparation of 5-[(tert-butox carbonyl)aminol-l-methyl-lH-Pyrazole-4-carboxylic acid O
N/ I OH

ZZ~ O CH3 A solution of ethyl5-[bis(tert-butoxycarbonyl)amino]-1-methyl-lH-pyrazole-4-carboxylate (8.0 g, 21.66 mmol) in ethanol (100 mL) was stirred under nitrogen as aqueous 1 N sodium hydroxide (108 mL) was added. The resulting mixture was stirred at 50 C for 64 h, cooled to ambient temperature and then evaporated in vacuo.
The pH was adjusted to 5-6 by slow addition of 2 N aqueous HCl. The product was extracted with ethyl acetate and then a 20% inixture of isopropanol in dichloromethane. The combined extracts were dried (Na2SO4) and evaporated in vacuo, and then toluene was added to the residue which was evaporated again to yield 3.5 g (67%) of pure dry product ready for the next step.

1H NMR (300 MHz, CD3OD-d4) b 7.82 (s, 1H), 3.75 (s, 3H), 1.5 (s, 9H); ES-MS
rn/z 241.9 [M+H]+, LCMS RT (min) 1.81.

Step 3: Preparation of 5-amino-N-(2 2-difluoro-1 3-benzodioxol-5- 1-1-methyl-IH-pyrazole-4-carboxamide O XF
N H
O
O
D

A solution of 5-[(tert-butoxycarbonyl)amino]-1-methyl-lH-pyrazole-4-carboxylic acid (1 g , 4.15 mmol), 2,2-difluoro-1,3-benzodioxol-5-amine (861 mg, 4.97 rnmol), triethylamine (1.19 mL, 8.55 mmol) and (1H-1,2,3-benzotriazol-l-yloxy)(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (PyBOP, 2.15 g, 4.15 mmol) in anhydrous dimethylformamide (20 mL) and dichloromethane (1 mL) was stirred at 60 C for 12 h under nitrogen and then cooled. The resulting solution was diluted with ethyl acetate and washed with water and then saturated brine. The organic layer was dried (Na2SO4) and evaporated in vacuo. The resulting residue was chromatographed using silica gel with 0 - 100% ethyl acetate in hexane to yield tert-butyl (4-{
[(2,2-difluoro-l,3-benzodioxol-5-yl)amino]carbonyl}-1-methyl-lH-pyrazol-5-yl)carbamate (500 mg, >60%
in purity) which was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (3 mL) and was stirred under nitrogen for 2 h and evaporated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated aqueous NaHCO3. The organic phase was dried (NkSO4), evaporated in vacuo and purified using silica gel with 0-80 %
ethyl acetate in hexanes to yield 250 mg of the title compound.

1H NMR (300 MHz, CD3OD-d4) 8 7.85 (bs, 1H), 7.70 (s, 1H), 7.25 (dd, 1H), 7.10(dd, 1H), 3.60 (s, 3H); ES-MS nt/z 297.2 [M+H]+, LCMS RT (inin) 3.03.

Intermediate B
Preparation of 5-amino-l-methyl-N-(2,2,3,3-tetrafluoro-2,3-dihydro-l,4-benzodioxin-6-yl)-1H-pyrazole-4-carboxaniide F

F
N~ ~ H ~ F

This intermediate can be prepared by using the method described above for the preparation of Intermediate A but using 2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-amine rather than 2,2-difluoro-1,3-benzodioxol-5-amine in Step 3. The pure product is characterized by NMR and LCMS spectroscopy.

Intermediate B-2 Preparation of 5-amino-l-methyl-N-(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)-1H-p_yrazole-4-carboxamide O ~ I O F
~
N/ H F F

This intermediate can be prepared by using the method described above for the preparation of Intermediate A but using 2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-amine rather than 2,2-difluoro-1,3-benzodioxol-5-amine in Step 3.

Intermediate B-3 Preparation of 5-amino-l-methyl-N-f4-(trifluoromethox )phenyll-4,5-dihydro-1H-n_yrazole-4-carboxamide F
O
j N,/D H F

This intermediate can be prepared by using the method described above for the preparation of Intermediate A but using 4-(trifluoromethoxy) aniline rather than 2,2-difluoro-1,3-benzodioxol-5-amine in Step 3.

Intermediate B-4 Preparation of 5-amino-l-methyl-N-r3-(trifluoromethoxv)phenyll-4,5-dihydro-1H-u_yrazole-4-carboxamide O F

N~ I H O F

This intermediate can be prepared by using the method described above for the preparation of Intermediate A but using 3-(trifluoromethoxy)aniline rather than 2,2-difluoro-1,3-benzodioxol-5-amine in Step 3.

Intermediate B-5 Preparation of 5-amino-l-methvl-N-{4-f(trifluoromethvl)thiolphenyll-1H-pyrazole-4-carboxamide F
N F
N, ~

This intermediate can be prepared by using the method described above for the preparation of Intermediate A but using 4-[(trifluoromethyl)thio] rather than 2,2-difluoro-1,3-benzodioxol-5-amine in Step 4.

Intermediate C
Preparation of [2-(aminocarbonyl)pyridin-4-y11methyl methanesulfonate CH
o ~ O 0 V~,N NH2 Step 1: Preparation of ethyl 2-(aminocarbonyl)isonicotinate N
A solution of ethyl isonicotinate (25.2 mL, 165 mmol) in formamide (200 mL) was stirred with ice/methanol bath cooling as concentrated sulfuric acid (8.80 mL, 165 mmol) was added. Ferrous sulfate heptahydrate (69 g, 248 mmol) and hydrogen peroxide (25.6 mL of 30% in water) were added slowly over 25 min in alternating portions such that the temperature of the mixture was kept between 8-10.5 C. During this addition small pieces of dry ice were added to the bath to keep the reaction temperature in the desired range.
After the addition was complete, the ice bath was removed and the dark mixture was stirred for 2 h without cooling. The mixture was then poured into a solution of trisodium citrate dihydrate (80.6 g) in water (700 mL) and then residues left in the reaction flask were washed out with a little methanol and water. The resulting mixture was rapidly stirred in a large flask as solid NaHCO3 was added slowly, portion-wise, until the mixture was basic. Some saturated aqueous NaHCO3 was added to make the mixture more basic and then it was vacuum filtered through Celite0 and the solids were washed down with three 200 mL portions of dichloromethane. The phases of the filtrate were separated and the aqueous layer was extracted twice with dichloromethane. The combined extract was dried (Na2SO4) and evaporated in vacuo. The resulting solid residue was washed with ether/hexane (200 mL, 1:30) twice with warming and sonication followed by cooling and filtration to yield 13.9 g (44%) of pure title compound. The wash solutions, which contained some highly contaminated desired product, were discarded.

1H NMR (300 MHz, DMSO-d,) 5 8.83 (d, 1H), 8.39 (d, 1H, meta coupling), 8.24 (bs, 1H), 8.00 (d, 1H), 7.81 (bs, 1H), 4.39 (q, 2H) and 1.37 ppm (t, 3H); ES-MS m/z 195.0 [M+H]+, HPLC RT (min) 1.83.

Step 2: Preparation of 4-(hydroxymeth yl)pyridine-2-carboxamide OH O

I ~ NH2 ~N

A slurry of ethyl2-(aminocarbonyl)isonicotinate (5.00 g, 25.8 mmol) in absolute ethanol (150 mL) was stirred under nitrogen as sodium borohydride (2.92 g, 77.2 mmol) was added. After 22 h stirring at ambient temperature, the reaction was carefully quenched by addition of 17 mL of saturated aqueous ammonium chloride followed by stirring until the bubbling stopped and then evaporation in vacuo to leave a white solid residue. Saturated aqueous sodium chloride (80 mL) was added followed by five extractions with 200 mL portions of ethyl acetate. Combined extracts were dried (Na2SO4) and evaporated in vacuo to yield 3.85 g (98%) of pure title compound as a white solid.

1H NMR (300 MHz, DMSO-d6) b 8.52 (d, 1H), 8.00 (s, 1H), 8.07 (bs, 1H), 7.46 (d, 1H), 7.60 (bs, 1H), 5.54 (t, 1H) and 4.60 ppm (d, 2H); ES-MS m/z 154.0 [M+H, weak signal]+, HPLC RT (min) 1.05.

Step 3: Preparation of [2-(aminocarbon~l)pyridin-4-yllmethyl methanesulfonate CH
O~1 I ~ NH2 ~N

4-(hydroxymethyl)pyridine-2-carboxamide (1.00 g, 6.57 mmol) was dissolved in ethyl acetate (80 mL) and then cooled to 0 C with stirring under nitrogen in an ice bath before triethylamine (1.37 mL, 9.86 mmol) was added, followed by methanesulfonyl chloride (0.66 mL, 8.54 mmol, added dropwise over 7 min). The ice bath was removed and the resulting suspension was stirred 2 h, and then the reaction mixture was poured into 60 mL water and stirred rapidly for 10 min. The phases were separated and the aqueous was extracted twice more with ethyl acetate. Each extract was washed with brine and the combined extracts were dried (Na2SO4) and evaporated in vacuo to yield 1.50 g (99%) of pure product as a fine white solid which turned pink on storage. Re-assay by NMR after such color change did not show significant decomposition.

1H NMR (300 MHz, DMSO-d6) 8 8.64 (d, 1H), 8.06 (s, 1H), 8.14 (bs, 1H), 7.6 (d, 1H), 7.70 (bs, 1H), 5.41 (s, 2H) and 3.33 ppm (s, overlaps with water in solvent).
Intermediate D
Preparation of {2-[(methylamino)carbonyllpyridin-4-yl}methyl methanesulfonate O~O O
I H,CH3 iN

This compound was prepared by using the method described above for Intermediate C but starting with methyl formamide rather than formamide in step 1 and methanesulfonic anhydride rather than methanesulfonyl chloride in step 3.

'H NMR (300 MHz, DMSO-d6) 8 8.80 (bs, 1H), 8.64 (d, 1H), 8.03 (s, 1H), 7.58 (d, 1H), 5.41 (s, 2H), 3.29 (s, 3H) and 2.80 ppm (d, 3H); ES-MS m/z 145.1 [M+H]+, HPLC
RT (min) 1.43.

Intermediate E
Preparation of 2-{[4-(chloromethyl)pyridin-2-yllamino}-2-oxoethyl acetate CI H O

I ~ N~OxCH3 N O

Step 1: Preparation of 4-(chlorometh~l)pyridin-2-amine CI
I ~ NH2 (2-Aminopyridin-4-yl)methanol (11.2 g, 90 mmol) was stirred in a flask with ice bath cooling as thionyl chloride (65.8 mL, 902 mmol) was slowly added. After about 10 mL was added, the temperature increased suddenly to about 50 C and addition was halted as the mixture was broken up so that stirring could continue as the rest of the thionyl chloride was added. The cooling bath was then removed and the reaction was stirred for 2 h at ambient temperature before it was evaporated in vacuo and then toluene was added twice and evaporated each time in vacuo to yield the hydrochloride salt of the title compound. A suspension of this material in dichloromethane (150 mL) was stirred with saturated aqueous sodium bicarbonate (150 mL) for 1.5 h. The phases were separated and the organic extract was washed twice with water, once with brine and then dried (Na2SO4) and evaporated in vacuo to yield 10.71 g (83%) of pure title compound.

'H NMR (300 MHz, DMSO-d6) 8 7.87 (d, 1H), 6.48 (d, 1H), 6.45 (s, 1H), 6.04 (s, 2H) and 4.60 ppm (s, 2H); ES-MS rn/z 143.2 [M+H]+, HPLC RT (min) 1.34.

Step 2: Preparation of 2- f f 4-(chloromethyl)pyridin-2-y11amino 1-2-oxoethyl acetate CI O
\ Ny'O'J~ CH3 I ~N O

A suspension of 4-(chloromethyl)pyridin-2-amine (2.50 g, 10 nunol) and triethylamine (11.7 mL) in dichloroethane (10 mL) was stirred under nitrogen with ice bath cooling as acetoxyacetyl chloride (1.86 mL, 17 minol) was added slowly over 10 min.
After 2 h stirring with cooling, TLC showed no starting material but three major product spots. The mixture was diluted with dichloromethane and washed with water and then brine. It was dried (Na2SO4) and evaporated in vacuo. The residue was purified by chromatography on silica gel using a gradient from 0-3% methanol in dichloromethane to yield 0.62 g(18%) of the correct and pure title compound.

1H NMR (300 MHz, DMSO-d6) b 10.75 (s, 1H), 8.30 (d, 1H), 8.10 (bs, 1H), 7.17 (d, 1H), 4.79 (s, 2H), 4.71 (s, 2H) and 2.13 ppm (s, 3H); ES-MS tn/z 243.1 [M+H]+, HPLC
RT (min) 1.87.

Intermediate F
Preparation of N-[4-(chloromethyl)pyridin-2-y11acetamide CI H

CN NuCH3 IOI
By using the methods described for preparation of Intermediate E and by substituting acetyl chloride instead of acetoxyacetyl chloride in step 2, Intermediate F was prepared from 2.30 g of 4-(chloromethyl)pyridin-2-amine and proportional amounts of other reagents. The yield of title compound was 2.0 g (67%) after silica gel chromatography. Even though examination of this material by NMR spectroscopy indicated that it was a mixture of the desired compound and the diacylated product N-acetyl-N-[4-(chloromethyl)pyridin-2-yl]acetamide (about 45:55), it was used as is in the next reaction and side products were separated by chromatography after the subsequent reaction.

'H NMR (300 MHz, CD2C12) 8 8.33 (bs, 1H), 7.41 (d, 1H), 7.30 (s, 1H), 7.10 (d, 1H), 4.65 (s, 2H) and 2.20 ppm (s, 3H); ES-MS rn/z 185.0 [M+H]+, HPLC RT (min) 1.16.
Signals for the contaminating diacyl compound show at 1H NMR (300 MHz, CD2C12) 8.56 (d, 1H), 8.18 (s, 1H), 78.24 (d, 1H), 4.75 (s, 2H) and 2.25 ppm (s, 6H);
ES-MS m/z no significant M+H+ion, HPLC RT (min) 0.97. Because of the closeness of the %
content of the two compounds, it is possible that some of the NMR peak assignments have been switched between the desired material and the contaminant.

Intermediate G
Preparation of N-[4-(chloromethyl)pyridin-2-yll-2-methoxyacetamide CI H
1I ~ NO,CH3 ~N O

By using the methods described for preparation of Intermediate E and by substituting 2-methoxyacetyl chloride instead of acetoxyacetyl chloride in step 2, Intermediate G was prepared from 731 mg of 4-(chloromethyl)pyridin-2-amine and proportional amounts of other reagents. The yield of pure title compound was 397 mg (45%) after silica gel chromatography using a gradient from 0-40% ethyl acetate in hexane.

1H NMR (300 MHz, CDC13) 8 9.00 (bs, 1H), 8.31 (d, 1H), 8.30 (s, 1H), 7.13 (d, 1H), 4.55 (s, 2H), 4.06 (s, 2H) and 3.51 ppm (s, 3H); ES-MS m/z 215.0 [M+H]+, HPLC

RT (min) 0.71.

Intermediate H
Preparation of N-[4-(chloromethyl)nyridin-2-yl1-2-(2-methoxyethoxy)acetamide CI H

CN N~O~/O'CH3 O

By using the methods described for preparation of Intermediate E and by substituting 2-(2-methoxyethoxy)acetyl chloride instead of acetoxyacetyl chloride in step 2, Intermediate H was prepared from 599 mg of 4-(chloromethyl)pyridin-2-amine and proportional amounts of other reagents. The yield of pure title compound was 314 mg (29%) after silica gel chromatography twice, first using a gradient from 2-3%
methanol in dichloromethane, and then a second chromatography of the best fractions using a gradient from 0-40% ethyl acetate in hexane.

1H NMR (300 MHz, CD2Cla) 8 9.39 (bs, 1H), 8.30 (d, 1H), 8.29 (s, 1H), 7.13 (d, 1H), 4.59 (s, 2H), 4.14 (s, 2H), 3.76 (t, 2H), 3.60 (t, 2H) and 3.44 ppm (s, 3H); ES-MS m,/z 259.1 [M+H]+, HPLC RT (min) 1.46.

Intermediate I
Preparation of N-[4-(chloromethyl)pyridin-2-y11-2-methoxypropanamide NO,CH3 N O

Step 1: Preparation of 2-methoxypropanoic acid H3C ~CH3 HOO
O

Sodium methoxide in methanol (25%, 16 mL) was added to a stirred solution of 2-bromopropionic acid (19.6 mmol) in methanol (5 mL) under nitrogen. The reaction was heated at 50 C under nitrogen overnight. The reaction was then concentrated under vacuum. The residue was brouglit to pH 1 by the addition of 1 N aqueous HCl and this solution was then extracted with ethyl acetate three times (70 mL, 25 mL, 10 mL). The combined organic layer was dried (Na2SO4) and then concentrated under vacuum to yield the title compound as a colorless oil 2.04 g (99%) which was of sufficient purity to be used without purification. 'H NMR (CD3OD) S 3.67 (q, 1H), 3.33 (s, 3H), and 1.33 ppm (d, 3H).

Step 2: Preparation of 2-methoxypropanoyl chloride ClQ/CH3 Q

2-Methoxypropanoic acid (2.04 g, 19.2 mmol) was dissolved in dichloromethane (3 mL) which was stirred under nitrogen as a drop of dimethylformamide was added.
Thionyl chloride was added dropwise into the reaction over 3 min and then the reaction was stirred at room temperature overnight. The reaction solution was concentrated in vacuo and the resulting pale yellow oil was placed under high vacuum to remove last traces of thionyl chloride. The yield of pure title compound was 303 mg (13%).

(CDC13) 8 4.10 (q, 1H), 3.48 (s, 3H), and 1.56 ppm (d, 3H).

Step 3: Preparation of N-f4-(chloromethyl)pyridin-2-yll-2-methoxypropanamide ci NH$C CH H \ Os 3 I ~N O

By using the methods described for preparation of Intermediate E (Step 2) and by substituting 2-methoxypropanoyl chloride instead of acetoxyacetyl chloride, Intermediate I
was prepared from 352 mg of 4-(chloromethyl)pyridin-2-amine and proportional amounts of other reagents. The yield of pure title compound was 341 mg (60%) after silica gel chromatography using a gradient from 0-30% ethyl acetate in hexane.

'H NMR (300 MHz, DMSO-d6) b 10.2 (bs, 1H), 8.30 (d, 1H), 8.17 (s, 1H), 7.16 (d, 1H), 4.77 (s, 2H), 4.00 (q, 1H), 3.26 (s, 3H), and 1.27 ppm (d, 6H).

Intermediate J
Preparation of N-f4-(chloromethyl)pyridin-2-yll-2-methoxy-2-methylpropanamide Ci H H3C CH3 \ N O~

Step 1: Preparation of 2-methoxy-2-methylpropanoic acid HOO

O

The procedure of Weizmann, Sulzbacher, and Bergmann as written in JACS
70,1153 (1948), which is hereby incorporated by reference, was used as follows: A
solution of potassium hydroxide (8.96 g, 159.7 mmol) in 5 mL of water and 20 mL of methanol was stirred with ice batli cooling under nitrogen as 1,1,1-trichloro-methylpropan-2-ol (7.10 g, 40.0 mmol) was carefully added dropwise over ten min.
Vigorous bubbling was observed as a white precipitate formed. The ice bath was removed after 15 min. The reaction was stirred at room temperature for 2 h then refluxed for 3 h.
The reaction was cooled to room temperature and the solids were then removed by filtration and rinsed with methanol (350 mL). The filtrate was concentrated under vacuum to remove methanol and the remaining aqueous layer was brought to pH 0 by the addition of aqueous HC1 then extracted with ethyl acetate (300 mL). The extract was dried (Na2SO4) and concentrated in vacuo to yield 4.11 g of crude product, which was purified by vacuum distillation to yield 2.28 g (48%) of the pure title coinpound as a colorless oil which was distilled at 105 C (28 mm Hg). 1HNMR (CDC13) 6 9.65 (s, 1H), 3.20 (s, 3H) and 1.32 ppm (s, 6H).
Step 2: Preparation of 2-methoxy-2-methylpropanoyl chloride C~~

By following the procedure of Intermediate I (Step 2) but using 2-methoxy-2-methylpropanoic acid (6.99 g, 59.2 mmol) rather than 2-methoxypropanoic acid and proportional amounts of other reagents the title compound was synthesized. The crude product was distilled in vacuo to yield 2.671 g (33%) of pure compound, bp 44-(38 mm Hg).
1HNMR (CDC13) 6 3.33 (s, 3H) and 1.51 ppm (s, 6H).
Step 3: Preparation of N-f4-(chloromethyl)pyridin-2-yll-2-methoxy-2-methylpropanamide ci HH3C CH3 N O

I ~N O

By using the methods described for preparation of Intermediate E (Step 2) and by substituting 2-methoxy-2-methylpropanoyl chloride instead of acetoxyacetyl chloride, Intermediate J was prepared from 1.04 g of 4-(chloromethyl)pyridin-2-amine and proportional amounts of other reagents. The yield of title compound was 1.23 g (69%) after silica gel chromatography using 30% ethyl acetate in hexane.

1H NMR (300 MHz, DMSO-d6) 8 9.41 (bs, 1H), 8.32 (d, 1H), 8.16 (s, 1H), 7.19 (d, 1H), 4.78 (s, 2H), 3.28 (s, 3H) and 1.36 ppm (s, 6H); ES-MS m/z 243.1 [M+H]+, HPLC
RT (min) 2.12.

Intermediate K
Preparation of N-[4-(chloromethvl)uvridin-2-vllmethanesulfonamide CI H
N'g ;CH3 I ~N O. 0 Step 1: Preparation of N-f4-(chlorometh y1)pyridin-2-yll-N-(methylsulfonyl) methanesulfonamide CI O~I

N'S;CH3 N O. .O

A solution of 4-(chloromethyl)pyridin-2-amine (500 mg, 3.51 mmol) and triethylamine (1.47 mL, 10.5 mmol) in ethyl acetate (4 mL) was stirred under nitrogen in a flask with ice bath cooling as methanesulfonyl chloride (0.81 mL, 10.5 mmol) was added dropwise. The reaction was then allowed to stir without cooling for 1 h before it was diluted with additional ethyl acetate, washed with water, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by chromatography on silica gel using an ethyl acetate/ hexane gradient to yield 860 mg (82%) of pure title compound.

1H NMR (300 Hz, CD2C12) 8 8.56 (d, 1H), 7.50 (d, 1H), 7.41 (s, 1H), 4.66 (s, 2H), and 3.55 ppm (s, 6H); ES-MS m/z 299.0 [M+H]+, HPLC RT (min) 2.08.
Step 2: Preparation of N-f4-(chloromethyl)pyridin-2-yllmethanesulfonamide CI H
\ N'S;CH3 A suspension of N-[4-(chloromethyl)pyridin-2-yl]-N-(methylsulfonyl)-methanesulfonamide (700 mg, 2.34 mmol) in methanol (10 mL) and aqueous sodium hydroxide (1 N, 11.7 mL, 11.7 nunol) was stirred at ambient temperature as the starting material dissolved over 10 min. After another 10 min the reaction was adjusted to a pH
between 3 and 6 by addition of aqueous hydrochloric acid (2 N) to precipitate the desired product as a white solid that was collected by filtration, washed with methanol and dried in vacuo. The yield of title compound was 250 mg (48%).

1H NMR (300 MHz, DMSO-d6) b 10.93 (bs, 1H), 8.21 (d, 1H), 7.02 (m, 2H), 4.73 (s, 2H), and 3.23 ppm (s, 3H); ES-MS m/z 221.1 [M+H]+, HPLC RT (min) 1.45.
Intermediate L
Preparation of N-[4-(chlorometh 1)pyridin-2-yl]-N'-ethylurea Ci H H
NuNCH3 N IOI

To 4-(chloromethyl)pyridin-2-amine (100mg, 0.70mmo1) in 3 mL DMF was added ethyl isocyanate (59 mg, 0.84 mmol) and the resulting mixture was stirred under nitrogen for 16 h. The reaction was diluted with EtOAc (15 mL) and washed with H20 three times, dried (Na2SO4) and evaporated in vacuo. The crude residue was purified by column chromatography on silica gel using 25% EtOAc in hexane to give 110 mg of N-[4-(chloromethyl)pyridin-2-yl]-N'-ethylurea (73 %).

1H NMR (DMSO-d6) S 9.22 (s, 1H), 8.14-8.16(m, 1H), 7.91-7.94 (m, 1H), 7.45 (d, J=0.8Hz, 1H), 6.93-6.95 (m, 1H), 4.70 (s, 2H), 3.12-3.14(m, 2H), 1.01-1.09(m, 3H) ppm;
LCMS: 214.1 [M+H]+, RT 0.47 min.

Intermediate M
Preparation of N-[4-(chloromethyl)nyridin-2-yll-N'-nhenylurea CI H H
NuN ~
~ N IOI ~ /

By using the methods described for preparation of Intermediate L and by substituting phenyl isocyanate instead of ethyl isocyanate, Intermediate M was prepared.
From 250 mg of 4-(chloromethyl)pyridin-2-amine and proportional amounts of other reagents the yield of title compound was 218 mg (47%) after silica gel chromatography using a gradient from 0-40 % ethyl acetate in hexane. Though there was evidence of contamination with the starting material 4-(chloromethyl)pyridin-2-amine in the NMR
spectrum, this material was used without further purification and side products were separated by chromatography after the next step.

'H NMR (300 MHz, DMSO-d6) b 10.25 (bs, 1H), 9.50 (bs, 1H), 8.29 (d, 1H), 7.95 (s, 1H), 7.52 (d, 1H), 7.27-7.36 (m, 2H), 7.0-7.1 (m, 2H), and 4.79 ppm (s, 2H); LCMS:
262.2 [M+H]+, RT 2.65 min.
Intermediate N
Preparation of N-[4-(chloromethyl)pyridin-2-_ 1]-N'-methylurea Ci H H
Ny N.CH3 N B
y using the methods described for preparation of Intermediate L and by substituting methyl isocyanate instead of ethyl isocyanate, Intermediate N was prepared.
From 180 mg of 4-(chloromethyl)pyridin-2-amine and proportional amounts of other reagents the yield of pure title compound was 42 mg (17%) after silica gel chromatography using a gradient from 0-50 % ethyl acetate in hexane followed by trituration of the residue with ether to remove a contaminant.

1H NMR (DMSO-d6) S 9.31 (s, 1H), 8.16 (d, 1H), 7.92 (bm, 1H), 7.40 (s, 1H), 6.93 (d, 1H), 4.69 (s, 2H) and 2.70 ppm (d, 3H); LCMS: 200.1 [M+H]+, RT 1.17 min.
Intermediate NN
Preparation of N'-[4-(chloromethyl)pyridin-2-yl]-N,N-dimethylurea ~ NuN.CH
N ICI s By using the methods described for preparation of Intermediate K and by substituting dimethylcarbamic chloride instead of methanesulfonyl chloride, Intermediate NN is prepared.
Intermediate 0 Preparation of 2,4-dichloro-6-(chloromethvl)pvrimidine CI
NYCI
IN
CI

This product was prepared similarly to the 5-methyl substituted analog described in Biorg. Med. Chena. 2002, 10, 525. A stirred suspension of 6-(chloromethyl)pyrimidine-2,4(1H,3H)-dione (5.2 g, 32.6 mmol) in POC13 (9.1 mL, 97.9 mmol) was refluxed for 16 h under nitrogen. The mixture was cooled and evaporated to leave a dark colored oil. Ice water was slowly added and the product was extracted into dichloromethane. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure to give 2,4-dichloro-6-(chloromethyl)pyrimidine (5 g) as a yellow oil. Though this product could be used in the next step with out purification, another batch prepared in the same way was further purified by chromatography to show the following NMR.

1H NMR (DMSO-d6) b 7.90 (s, 1H) and 4.78 ppm (s, 2H).
Intermediate P
Preparation of 2-chloro-4-(chloromethyl)pyridine CI
CI
~N

Step 1: Preparation of (2-chloropyridin-4-yl)methanol OH
CI

I ~N

A sample of inethyl2-chloroisonicotinate (5.00 g, 29.14 mmol) was dissolved in mL THF, treated with 10 drops of methanol, and cooled to 0 C. The solution was treated with lithium borohydride solution (21.86 mL of 1 M in THF, 43.71mmol) and then allowed to warm to room temp. After 4 h the solution was cooled to 0 C and quenched with 1 N HC1 solution. The pH was adjusted to pH 10 with 1 N NaOH solution, and the reaction mixture was extracted with EtOAc. The organic extracts were washed with brine and concentrated in vacuo yielding 2.96 g (70.8%) of product.
1H NMR (300 MHz, CD3CN) S 8.32 (d, 1 H), 7.39 (s, 1 H), 7.29 (d, 1 H), 4.62 (s, 2 H) and 3.53 ppm (bs, 1 H).

Step 2: Preparation of 2-chloro-4-(chloromethvl)p ri~
CI
CI
I ~N

A sample of (2-chloropyridin-4-yl)methanol (110.0 mg, 0.77 mmol) was dissolved in anhydrous THF (1.5 mL), treated with N,N-diisopropylethylamine (0.29 mL, 1.69 mmol) and cooled to -78 C. Methanesulfonyl chloride was added (0.07 mL, 0.84 mmol), and the reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was then diluted with dichloromethane and washed with water.
The organic layer was dried over NaZSO4 and concentrated in vacuo yielding the title compound (110.0 mg, 88.6%).

1H NMR (300 MHz, CD3CN) 8 8.40 (d, 1 H), 7.49 (s, 1 H), 7.39 (d, 1 H) and 4.63 ppm (s, 2 H); ES-MS m/z 183.2 [M+Na]+, HPLC RT (min) 2.30.

Intermediate PP
Preparation of f2-(2,5-dimethyl-lH-pyrrol-1-yl)pyridin-4- llXl methanesulfonate H3C.s.O 3 N

Step 1: Preparation of f2-(2 5-dimethyl-lH-pyrrol-1-yl)pyridin-4-yllmethanol O
I ~ N

~ N CH3 (2-aminopyridin-4-yl)methanol (7.5 g, 60.41 mmol), hexane-2,5-dione (7.58 g, 66.46 mmol) and p-toluenesulfonic acid monohydrate(1.14 g, 6.04) was dissolved in Toluene (10 mL) in a flask fitted with a Dean Stark trap. The solution was heated to reflux at 135 C for 16 h. The solvents were evaporated and ethyl acetate was added. The organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified using silica gel with a gradient elution from 10-50% ethyl acetate in hexanes to yield 10.2 g (83%) of product.

'H NMR (300 MHz, CD2C12-d2) 8 8.52 (dd, 1H), 7.30 (m, 1H), 7.22 (m, 1H), 5.85(s, 2H), 4.78 (s, 2H), 2.08 (s, 6H); ES-MS m/z 203.2[M+H]+, LCMS RT (min) 2.04.
Step 2: Preparation of f2-(2 5-dimethyl-lH-p rrol-1-yl)pyridin-4- 1lyI
methanesulfonate O~ //o H C
H3C' S\C 3 I ~ N ~
~ N CH3 A sample of [2-(2,5-dimethyl-lH-pyrrol-1-yl)pyridin-4-yl]methanol (6.80 g, 33.62 mmol) was dissolved in anhydrous dichloromethane (30 mL), treated with triethylamine (14.06 mL, 100.9 mrnol) and cooled to 0 C. Methanesulfonyl chloride was added (3.90 mL, 50.43 mmol), and the reaction inixture was allowed to slowly warm to room temperature overnight. The reaction mixture was then diluted with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo and the residue was purified over silica gel using 10-60% ethylacetate in hexanes as eluant to yield the title compound (7.5 g, 80%).

'H NMR (300 MHz, CD2C12-d2) 8 8.65 (dd, 1H), 7.35 (m, 1H), 7.25 (m, 1H), 5.88(s, 2H), 5.30 (s, 2H), 3.10 (s, 3H), 2.12 (s, 6H); ES-MS m/z 281.1[M+H]+, LCMS RT
(min) 2.67.

Intermediate 0 Preparation of 4-(chloromethvl)-N-(4-methyl-1,3-thiazol-2-yl)pyridin-2-amine CI H
S
N N /

Step 1: Preparation of 4-({ [tert-butyl(dimethyl)silylloxy}methyl)pyridin-2-amine H3C J<CH3 ,Si CH3 A solution of (2-aminopyridin-4-yl)methanol (5.0 g, 40 mmol), tert-butyldimethylsilyl chloride (6.07 g, 40 mmol), N-ethyl-N-isopropylpropan-2-amine (7.0 mL, 40 mmol) and N,N-dimethylpyridin-4-amine (0.49 g, 4 mtnol) in dichloromethane (50 mL) was stirred 2 days at ambient temperature under nitrogen. The resulting reaction mixture was washed in sequence with aqueous sodium hydroxide (1 N), water and brine.
It was then dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed on silica gel using 50 % ethyl acetate in hexane to yield pure title compound (5.47 g).

1H NMR (300 MHz, CD3CN) $ 7.75 (m, 1H), 6.39 -6.48 (m, 2H), 4.70 (bs, 1H), 4.
50 (s, 2H), 0.83 (s, 9H) and 0.03 ppm (s, 6H); ES-MS m/z 239.3 [M+H]+, HPLC RT
(min) 2.35.

Step 2: Preparation of N-({ f4-({ ftef-t-butyl(dimethyl)sil ly lox }~yl)pyridin-2-yll amino }carbonothioyl)benzamide 3 ~--CH3 H3C-Si-CH3 4 ~ ~ O

N H H I \
/
A solution of 4-({ [tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-amine (2.00 g, 8.39 mmol) and benzoyl isothiocyanate (1.51 g, 9.23 mmol) in toluene (20 mL) was heated to 85 C for 12 h. The solvent was removed by evaporation in vacuo and the residue was purified by chromatography on silica gel using a gradient from 0-10% ethyl acetate in hexane to yield pure title coinpound as a yellow oil which solidified on standing (2.68 g, 79%).

1H NMR (300 MHz, CD3OD) S 8.79 (bs, 1H), 8.18 (d, 1H), 7.83 (m, 2H), 7. 50 (m, 1H), 7.40 (m, 2H), 7.04 (m, 1H), 4.68 (s, 2H), 0.82 (s, 9H), and 0.03 ppm (s, 6H); ES-MS in/z 402.0 [M+H]+, HPLC RT (min) 4.24.

Step 3: Preparation of N-r4-( f(tert-butyl(dimeth ly )sil l~loxy}meth ~1)pyridin-2-yllthiourea H3C\I/CH3 O

A solution of N-({ [4-({ [tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-yl]amino}carbonothioyl)benzamide (1.00 g, 2.49 mmol) in absolute ethanol (15 mL) was stirred with potassium carbonate (0.344 g, 2.49 mmol) and heated to reflux under nitrogen for 16 h,after which the reaction mixture was filtered and the filtrate was evaporated under vacuum to give crude title compound (670 mg, > 100%) as a white solid which was carried on to the next step without purification.

1H NMR (300 MHz, DMSO-d6) b 10.55 (bs, 2H), 8.75 (bs, 1H), 8.05 (d, 1H), 7.10 (s, 1H), 6.83 (d, 1H), 4. 60 (s, 2H), 0.83 (s, 9H) and 0.03 ppm (s, 6H); ES-MS
m/z 298.2 [M+H]+, HPLC RT (inin) 3.25.

Step 4: Preparation of { 2- f(4-methyl-1 3-thiazol-2-yl)aminolpyridin-4-yl }
methanol OH H

N N N /

A solution of N-[4-({ [teyt-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-yl]thiourea (crude material, 650 mg) and 1-chloroacetone (0.18 mL, 2.18 mmol) in ethanol (10 mL) was refluxed under nitrogen for 16 h and cooled. A white/pink solid was collected by filtration and washed with ethanol. The filtrate was evaporated in vacuo to yield a second white/pink solid. Comparison of the NMR of the two solids indicated that they were both the title compound and were pure enough (about 90%) to carry on to the next step without further purification (combined residue yield 516 mg, > 100 %).

1H NMR (300 MHz, DMSO-d6) S 8.13 (d, 1H), 7.05 (s, 1H), 6.83 (d, 1H), 6. 58 (s, 1H), 4.42 (s, 2H) and 2.18 ppm (s, 3H); ES-MS nz/z 222.2 [M+H]+, HPLC RT (min) 1.41.

Step 5: Preparation of 4-(chloromethyl)-N-(4-methyl-1,3-thiazol-2-yl)pyridin-2-amine CI H
N S
I N NII

A mixture of {2-[(4-methyl-1,3-thiazol-2-yl)arnino]pyridin-4-yl}methanol (200 mg, 0.9 mmol) and thionyl chloride (0.66 mL, 9.04 mmol) was stirred for 3 h and then evaporated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate. The aqueous layer was back extracted twice with ethyl acetate and then twice with a mixture of isopropanol, ethyl acetate and dichloromethane (1:8:1). The combined extracts were dried (Na2SO4) and concentrated in vacuo.
The resulting residue was mixed with methanol, evaporated and then mixed with ethyl acetate and then evaporated again to yield the title compound as a light pink solid (200 mg, 92%) which was taken on to the next step as a crude solid.

1H NMR (300 MHz, CD2Cl2) 8 8.30 (m, 1H), 6.98 (s, 1H), 6.90 (m, 1H), 6. 50 (s, 1H), 4.55 (s, 2H) and 2.33 ppm (s, 3H); ES-MS rnJz 240.2 [M+H]+, HPLC RT (min) 1.14.
Intermediate R
Preparation of N-(f f 4-(chloromethyl)pyridin-2-yllaminolcarbonyl)benzamide CI H ~
\ N~N \ I
I ~N IOI O

By using the methods described for preparation of Intermediate L and by substituting benzoyl isocyanate instead of ethyl isocyanate and using dichloromethane rather than DMF as solvent, Intermediate R was prepared. The product, which separated from the reaction mixure as a solid, was collected by filtration and washed with dichloromethane.

1H NMR (DMSO-d6) 8 11.01 (s, 1H), 10.98 (bs, 1H), 8.06 (d, 1H), 7.82 (s, 1H), 7.73 (d, 2H), 7.37 (t, 1H), 7.25 (t, 2H), 6.90 (d, 1H), and 4.52 (s, 2H).

Preparation of Compounds of the Invention Example 1 Preparation of 4-f [(44 [(2,2-difluoro-1,3-benzodioxol-5-vl)aminol carbonyll-1-methyl-lH-pyrazol-5-yl)aminolmethyl}-N-methylp_yridine-2-carboxamide N O
N
H
N NH O
CH3 ~ N.CH3 ~ ~N H

A solution 5-amino-N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-lH-pyrazole-4-carboxamide (Intermediate A, 280 mg, 0.95 mmol), sodium iodide (283 mg, 1.89 mmol), and 2,6-di(tert)butyl-4-methylphenol (10 mg) in dry dimethylformamide (1.5 mL) was stirred under nitrogen as {2-[(methylamino)carbonyl]pyridin-4-yl}methyl methanesulfonate (Intermediate D, 461 mg, 1.89 mmol) was added. The resulting solution was stirred at 60 C in a foil wrapped flask for 20h. The resulting solution was evaporated and then diluted with 1 mL methanol and injected in two portions on a 150/20 mm C18 HPLC column using a gradient from 10-50 % acetonitrile in water (plus 0.05%
trifluoroacetic acid). The best fractions containing the desired material, as identified by LCMS, were combined, mixed with saturated NaHCO3, and extracted three times with dichloromethane. The combined extracts were dried (Na2SO4) and evaporated in vacuo to yield 90 mg (21%) of pure title compound.

1H NMR (300 MHz, CD3OD-d4) 8 8.50 (d, 1H), 8.10 (s, 1H), 7.85 (s, 1H), 7.70 (m, 1H), 7.55 (d, 1H), 7.25 (m, 1H), 7.10 (m, 1H), 4.65 (s, 2H), 3.70 (s, 3H), 2.95 (s,3H); ES-MS
m1z 445.3 [M+H]+, LCMS RT (min) 2.87.

Example 2 Preparation of 5-{[(2-chloropyridin-4-yl)methyllaminol-N-(2,2-diflnoro-1,3-benzodioxol-5-yl)-1-methyl-lH-pyrazole-4-carboxamide O OXF
F
N O
H
N NH
CHg Cl N
Step 1: Preparation of ethyl 5-(foimylamino)-1-methyl-lH-pyrazole-4-carboxylate O

N

O
A solution of formic acid (4ml, 106.02mmo1) and acetic anhydride (6m1, 63.59mrnol) was added to a solution of ethyl5-amino-l-methyl-lH-pyrazole-4-carboxylate (5.OOg, 29.55mmo1) in dry THF (30mL) and allowed to stir at room temperature for 16 h. The reaction mixture was then diluted with EtOAc and washed with concentrated NaHCO3 solution, followed by water, and then brine. The organic layer was dried over Na2SO4 and concentrated ira vacuo yielding 4.16g (71.4 Io) crude product. This material was used without further purification.

1H NMR (300 MHz, CD3CN) 8 8.32 (bs, 1H), 7.78 (s, 1H), 4.23 (q, 2H), 3.68 (s, 3H), 1.25 (t, 3H); ES-MS m/z 198.0 [M+H]+, HPLC RT (min) 1.41.
Step 2: Preparation of ethyl5-f((2-chloroi2yridin-4-yl)methyll(formyl)aminol-l-methyl-lH-pyrazole-4-carbox. ~~
O

N

CI
~N

A solution of crude ethyl5-(formylamino)-1-methyl-lH-pyrazole-4-carboxylate (3.OOg, 15.21mmo1) from step 1 in dichloromethane (30m1) was treated with diazabicyclo(5.4.0)undec-7-ene (3.41m1, 22.82mmo1) and allowed to stir at room temperature for 30 minutes. 2-Chloro-4-chloromethylpyridine (4.93g, 30.43mmol) was added, and the reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was then diluted with DCM and washed with concentrated NaHCO3 solution, followed by water, then brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude residue was washed with ether, and the ether washings were concentrated and triturated with hexanes. The residue was again concentrated yielding 3.93g (80.1%) product as a thin oil.

'H NMR (300 MHz, CD3CN) 8 8.30 (d, 1H), 8.23 (s, 1H), 7.85 (s, 1H), 7.33 (s, 1H), 7.22 (d, 1H), 4.80 (bs, 2H), 4.17 (q, 2H), 3.67 (s, 3H), 1.23 (t, 3H); ES-MS m/z 323.1 [M+H]+, HPLC RT (min) 2.31.

Step 3: Preparation of 5-f r(2-chloropyridin-4-yl)methyllan-iinol-l-methyl-lH--Dyrazole-4-carboxvlic acid O
N OH
N

~ ~ CI
~N
A solution of ethyl 5-[[(2-chloropyridin-4-yl)methyl](formyl)amino]-1-methyl-lH-pyrazole-4-carboxylate (3.93g, 12.18mmo1) in THF (25mL), MeOH (5mL), and water (5mL) was treated with LiOH (2.91 g, 1221.77mmo1) and allowed to stir at 80 C
overnight. The reaction mixture was then cooled to room temperature, and the pH was adjusted to three using 1N HC1. The reaction mixture was then diluted with EtOAc and washed with water, brine, and then dried over Na2SO4. Concentration of the ethyl acetate solution in vacuo gave crude product, which was triturated with ether yielding 2.Og (61.6%) product.

1H NMR (300 MHz, CD3CN) 8 8.32 (d, 1H), 7.56 (s, 1H), 7.38 (s, 1H), 7.28 (d, 1H), 6.18 (bm, 1H), 4.59 (d, 2H), 3.64 (s, 3H); ES-MS nz/z 267.1 [M+H]+, HPLC
RT
(min) 1.66.

Step 4: 5-f f(2-chloropyridin-4-yl)methyllaminoI -N-(2 2-difluoro-1 3-benzodioxol-5-yl)-1-methyl-1 H-pyrazole-4-carboxamide O O
F
NN N ~
% H O F

~ ~ cl ~N
A solution of 5-{[(2-chloropyridin-4-yl)methyl]amino}-1-methyl-1H-pyrazole-4-carboxylic acid (50.0mg, 0.19mmo1) in dry DMF (3mL) was treated with N,N-diisopropylethylamine (0.l0mL, 0.56minol), followed by PyBOP (97.57mg, 0.19mmol) and allowed to stir for 30 minutes. 5-Amino-2, 2-difluorobenzo-1,3-dioxole (64.91mg, 0.37mmol) was added, and the reaction mixture was allowed to stir for 16 h at 60 C. The reaction mixture was then diluted with EtOAc, and the organics were washed with concentrated NaHCO3 solution, followed by water, and then brine. The organics were then dried over Na2SO4 and concentrated in vacuo. The crude residue was triturated with hot hexanes yielding 55.0mg (68.6%) product.

1H NMR(300 MHz, CD3CN) S 8.43 (bs, 1H), 8.29 (d, 1H), 7.75 (d, 2H), 7.40 (s, 1H), 7.23-7.32 (m, 2H), 7.17 (d, 1H), 6.76 (bs, 1H), 4.53 (d, 2H), 3.68 (s, 3H); ES-MS
in/z 422.0 [M+H]+, HPLC RT (min) 3.12.

Example 3 Preparation of N-(2,2-difluoro-1,3-benzodioxol-5-yl)-5-[(f2-r(2-hydroxyethyl) aminolnyridin-4-yl}methyl)aminol-l-methyl-lH-pyrazole-4-carboxamide O O
F
N~ N
~\~
N H O r z/OH
~ ~
F H
~
F OH N
F
A solution of 5-{[(2-chloropyridin-4-yl)methyl]amino}-N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-lH-pyrazole-4-carboxamide (100.0mg, 0.24mmol) in pyridine (1mL) was treated with ethanolamine (0.50mL, 8.28mmol) and heated to in a sealed tube for 6 h. The reaction mixture was then allowed to cool to room temperature overnight. It was then diluted with water and extracted with EtOAc. The organic extracts were washed with water, dried over Na2SO4, and concentrated in vacuo.
Purification of the crude residue by HPLC (10-90% MeCN in water gradient containing 0.1% TFA) gave 23.0 mg (17.3%) of the title compound as the TFA salt.

1H NMR (300 MHz, CD3CN) S 8.40 (bs, 1H), 7.67-7.78 (m, 3H), 7.27 (d, 1H), 7.18 (d, 1H), 7.02 (s, 1H), 6.78 (d, 1H), 4.57 (s, 2H), 3.6-3.71 (m, 4H), 3.38 (m, 2H);
ES-MS a/.z 447.2 [M+H]+, HPLC RT (min) 2.23.

Examples 3-a to 3-e in Table A were made using the procedure of Example 2 (step 4) and Example 3 by substituting the appropriate starting materials:

Table A

Ex. Structure Name LC-MS LCMS
No [M+H]+ RT (min) O
H \ ~ ~F
F

H 5-[({2-[(2-N
hydroxyethyl)amino]pyridin-4-N oH yl}methyl)amino]-1-methyl-N-F F o [4-(trifluoromethoxy)phenyl]-oH 1 H-pyrazole-4-carboxamide 3-a F trifluoroacetate (salt); 451.2 2.28 o _ p F
NH \ ) ~-F

5-[({2-[(2,3-/ \ N OH dihydroxypropyl)amino]pyridin -N oH 4-yl}methyl)amino]-1-methyl-F F o N-[4-(trifluoromethoxy)phenyl]
AoH 1 H-pyrazole-4-carboxamide 3-b o F trifluoroacetate (salt ; 481.2 2.27 ~ O F
H \ ~ F
N N H o F ~F
H 3c 5-[({2-[(2-hydroxyethyl)amino]pyridin-4-/ \ rHV yI}methyl)amino]-1-methyl-N-N ~oH (2,2,3,3-tetrafluoro-2,3-F o dihydro-1,4-benzodioxin-6-yl)-F~oH 1 H-pyrazole-4-carboxamide 3-c F trifluoroacetate (salt); 497.2 2.51 C ~ O F
NH \ ~ F
O~F
H3C NH F 5-[({2-[(2,3-dihydroxypropyl)amino]pyridin / \ N OH 4-yl}methyl)amino]-1-methyl-N o ~oH N-(2,2,3,3-tetrafluoro-2,3-F F dihydro-1,4-benzodioxin-6-yl)-oH 1 H-pyrazole-4-carboxamide 3-d 0 F trifluoroacetate (salt); 527.2 2.46 NH \/'~ F
~
'F

N-(2,2-difluoro-1,3-/ \ N OH benzodioxoi-5-yi)-5-[({2-[(2,3-N ~ OH dihydroxypropyl)amino]pyridin F
o 4-yI}methyl)amino]-1-methyl-F~oH 1 H-pyrazole-4-carboxamide 3-e F trifluoroacetate salt ; 477.1 2.2 Example 4 Preparation of inethyl4-{[(4-{[(2,2-difluoro-l,3-benzodioxol-5-yl)aminolcarbonyl}-1-methyl-lH-pyrazol-5-yl)aminolmethyl}pyridine-2-carboxylate O ~ I ~F
N~ I N O
H
N NH O
CH3 I ~ O,Me ~N
Step 1: Preparation of 4-{r(4-{r(2,2-difluoro-1,3-benzodioxol-5-yl)amino1carbonylL-1-methyl-IH-pyrazol-5-yl)aminolmethyllpyridine-2-carboxamide O :I ~F
N~ I N O
, H
N NH O

V~, NH2 Th e title compound can be prepared by the following method. A solution of 5-amino-N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-lH-pyrazole-4-carboxainide (Intermediate A), sodium iodide, and 2,6-di(tef t)butyl-4-methylphenol in dry dimethylformamide can be stirred under nitrogen as [2-(aminocarbonyl)pyridin-4-yl]methyl methanesulfonate (Intermediate C) added. The resulting solution isstirred at 60 C in a foil wrapped flask for 20h. The resulting solution evaporated and then diluted with methanol and injected on a 150/20 mm C 18 HPLC column using a gradient from 10-50 % acetonitrile in water (plus 0.05% trifluoroacetic acid). The best fractions containing the desired material, as identified by LCMS, are combined, mixed with saturated NaHCO3, and extracted three times with dichloromethane. The combined extracts are dried (Na2SO4) and evaporated in vacuo to yield pure title compound.

Step 2 Preparation of methyl 4-{ [(4-{ f(2 2-difluoro-1 3-benzodioxol-5-yl)aminolcarbonyl i methyl-1 H-pyrazol-5-yl)aminolmethyllpyridine-2-carboxylate 0 ~ ~ XF
N~ I N O
, H
N NH O
, e CH3 V~, O,M

A suspension of 4-{[(4-{[(2,2-difluoro-l,3-benzodioxol-5-yl)amino]carbonyl}-1-methyl-lH-pyrazol-5-yl)amino]methyl}pyridine-2-carboxamide in 1.2 mL
methanol and N,N'-dimethylformamide dimethylacetal is heated with stirring in a sealed vial at 50 C.
After 2 h heating the solution is evaporated in vacuo and the residue is chromatographed on silica gel with a gradient from 0-1% methanol in dichloromethane to yield pure title compound.

Example 5 Preparation of 4-f[(4-{[(2,2-difluoro-1,3-benzodioxol-5-vl aminolcarbonyl}-1-methyl-1H-pyrazol-5-yl)aminolmethyl}-N-(4-pyrrolidin-l-ylbutyl)pyridine-2-carboxamide O C C~F
N~ I N O
H
N NH O
H3C \ N
I
~ ~N H

A slurry of 4-{ [(4-{ [(2,2-difluoro-1,3-benzodioxol-5-yl)amino]carbonyl}-1-methyl-lH-pyrazol-5-yl)amino]methyl}pyridine-2-carboxamide (Product from example 4 step 1) (95 mg, 0.21 mmol) in methanol (0.60 mL) is treated as in Example 4, step 2 to prepare a solution of inethyl4-{ [(4-{ [(2,2-difluoro-1,3-benzodioxol-5-yl)amino]carbonyl }-1-methyl-lH-pyrazol-5-yl)amino]methyl }pyridine-2-carboxylate, which isused directly and addition of 4-pyrrolidin-1-ylbutan-l-amine (266 mg, 1.87 mmol) and stirring at 65 C for 16 h. The reaction solution is purified by HPLC using direct injection, in three portions, on a YMC-Pack Pro C 18 column (150 x 20 mm) and is eluted at 20 mL/min with a gradient from 10-50 % acetonitrile in water plus 0.05% TFA.

Pure fractions from each injection are combined, made basic by addition of sodium bicarbonate and extracted with ethyl acetate. Combined extracts are dried (NkSO4) and evaporated in vacuo to yield pure title compound Example 6 Preparation of N-(2,2-difluoro-1,3-benzodioxol-5-vl)-5-F({2r(methox.yacetyl)aminol pyridin-4-yl}meth_yl)aminol-l-methyl-lH-pvrazole-4-carboxamide O a ><F
N~ N O
H
N NH H
CH3 \ N OCH3 I ~N O~

This material is prepared using the same method described for Example 1 but starting with 4-amino-N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1,3-thiazole-5-carboxamide (Intermediate A) and proportionate amounts of Intermediate G rather than Intermediate D
and also proportional amounts of the other reaction components. The reaction mixture is heated to 60 C in a foil wrapped flask overnight before crude product isolated. This material is purified by chromatography on silica gel using a gradient from 0-60 % ethyl acetate in hexane to yield final product.

Example 7 Preparation of 1-methyl-5- f({2- f(methylsulfonyl)aminolnyridin-4-yl}methyl)aminol-N-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-1H-pyrazole-4-carboxamide F
O a~:F
O N F

N NH H
CH3 N, CH3 tN pO'S

The title compound is prepared using the same method described for Example 1 but starting with 5-amino-l-methyl-N-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-1H-pyrazole-4-carboxamide (Intermediate B) rather than 5-amino-N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-lH-pyrazole-4-carboxamide (Intermediate A) and proportionate amounts of N-[4-(chloromethyl)pyridin-2-yl]methanesulfonamide (Intermediate K) rather than Intermediate D and also proportional amounts of the other reaction components. The reaction mixture is heated to 60 C in a foil wrapped flask for 16 h and then cooled. The reaction mixture is diluted with ethyl acetate, washed with water, dried (Na2SO4) and evaporated in vacuo. The crude product is purified by preparative HPLC to yield pure title compound.

Example 8 Preparation of 5-{ f (2-{[(ethylamino)carbonyllamino}pyridin-4-yl)methyllamino}-1-methyl-N-(2,2,3,3-tetrafluoro-2,3-dihydro-l,4-benzodioxin-6-yl)-1H-pyrazole-4-carboxamide F
O / I O F
iF
N ~ N O F
, H
N NH H H
CH3 N~r N,_,-CH3 N O

Step 1 Preparation of 5-({[2-(2,5-dimethyl-lH-Ryrrol-l-yl)pyridin-4-yllmethyl}amino)-1-inethyl-N-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-1H-pyrazole-4-carboxami.de F

:t-F
N// I NH Me O F
N NH
I --Me N ~
I , N Me The title compound was prepared using the saine method described for Example 2 using steps 1, 2, 3, and 4. In Step 2, intermediate PP was used in place of intermediate P.
1H NMR (300 MHz, CD3OD-d4) Fi 8.45 (d, 1H), 7.85 (s, 1H), 7.62 (m, 2H), 7.45 (m, 1H), 7.35 (m, 1H), 7.20 (m, 2H), 5.75 (s, 1H), 4.70 (s, 2H), 3.75 (s, 3H), 1.93 (s, 6H);
ES-MS rrzlz 485.1 [M+H]+, LCMS RT (min) 3.45.

Step 2 Preparation of 5-{f(2-aminopyridin-4- 1)methyllamino}-1-methyl-N-(2 2 3 tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-y1)-1 H-pyrazole-4-carboxamide F
O O IF
N~ ~ N O F
F
H
N NH

I ~N

To a solution of 5-({[2-(2,5-dimethyl-lH-pyrrol-1-yl)pyridin-4-yl]methyl}amino)-1-methyl-N-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-1 H-pyrazole-carboxamide (340 mg, 0.64 mmol) in ethanol (3 mL) was added water (1 mL), hydroxylamine hydrochloride (445 mg, 6.41mmol), followed by triethyl amine (0.18 mL).
The mixture was heated to reflux for 5 h and then cooled. The mixture was diluted with EtOAc and extracted with saturated NaHCO3. The organic layer was dried, evaporated and purified over silica gel using a 0-10% MeOH in DCM as a gradient to yield 222 mg (77%) of white solid.

1H NMR (300 MHz, CD3OD-d4) 8 7.85 (s, 1H), 7.79 (m, 2H), 7.42 (m, 1H), 7.20 (d, 1H), 6.58 (m,2H), 4.44 (s,2H), 3.74 (s,3H); ES-MS m1z 453.0 [M+H]+, LCMS
RT
(min) 2.50.
Step 3 Preparation of 5-{f(2-{r(ethylamino)carbonyllaminolpyridin-4-l)~yl1aminol-1-methyl-N-(2,2,3,3 -tetrafluoro-2,3-dihydro-1,4-benzodioxin-6- l)-1 pyrazole-4-carboxamide F
O / I O F
IF
N ~ N O F
H
N NH H H
CH3 Ny N,,_,CH3 To a solution of 5-{[(2-aminopyridin-4-yl)methyl]amino}-1-methyl-N-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-1H-pyrazole-4-carboxamide (100 mg, 0.22 mmol) in dichloroethane (1 mL) was added ethyl isocyanate (0.3 mL, 3.33 rnmol). The mixture was stirred at room temperature for 72 h. The solid precipitated out as the reaction proceeded. Ether (2mL) was added to the reaction mixture and the solid was filtered. The solid was washed with methanol (1 mL to remove any remaining starting material) and again with ether (2 mL) before evaporation to give the desired product (62 mg, 53%).
1H NMR (300 MHz, DMSO-d6) 8 9.80 (s, 1H), 9.12 (s, 1H), 8.05 (m, 2H), 7.88 (m, 1H), 7.82 (s, 1H), 7.45 (m, 1H), 7.40 (m, 1H), 7.30 (bs, 1H), 6.98 (t, 1H), 6.80 (d, 1H), 4.54 (d, 2H), 6.05 (s, 3H), 3.15 (m, 2H), 1.02 (t, 3H); ES-MS n2/z 524.1 [M+H]+, LCMS
RT (min) 2.71.
The compounds of examples 13, 14, and 15 as shown in Table B were made according to this method substituting the appropriate starting materials.

Example 9 Preparation of 1-methyl-5-1[(2-{ [(methylamino)carbonyllaminolpyridin-4-yl methyllaminol-N-(2 2 4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)-1H=pyrazole-4-carboxamide p O F I--F

N I C
N ~ H F F
N NH H H
CH3 I ~ N~N,CH

~N O 3 The title compound was prepared using the same method described for Example 2 using steps 1, 2, 3, and 4. In Step 2, intermediate N was used in place of 2-Chloro-4-chloromethylpyridine. In Step 4, the appropriate aniline was also substituted to give the title compound.
1H NMR (300 MHz, CD3OD-d4) S 8.25 (s, 1H), 8.15 (m, 1H), 7.90-7.97 (m, 2H), 7.32-7.37 (m, 1H), 7.12 (s, 1H), 6.94-6.97 (m, 1H), 4.60 (s, 2H under the water peak), 3.75 (s, 3H), 2.88 (s, 3H), ES-MS m/z 510.0 [M+H]+, LCMS RT (min) 2.67.
Examples 17, 18, and 19 as shown in Table B were made according to this method substituting the appropriate starting materials.

Examnle 10 Preparation of 5-r({2-[(aminocarbonyl)aminolRyridin-4-yl}methyl)aminol-N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-lH-pray zole-4-carboxamide O O ,F
O~F
N'/ ~ H
N NH H
CH3 Ny NH2 N O

The title compound was prepared using the same method described for Example 2 using steps 1, 2, 3, and 4. In Step 2, intermediate R was used in place of 2-Chloro-4-chloromethylpyridine. In Step 3, the hydrolysis also removes the benzoyl group along with the formyl group and hydrolysis of the ester.

1H NMR (300 MHz, CD3OD-d4) S 8.18 (d, 1H), 7.85 (s, 1H), 7.70 (m, 1H), 7.38 (m, 1H), 7.32 (m, 1H), 7.20 (m, 1H), 7.13 (m, 1H), 4.75 (s, 2H), 3.74 (s, 3H);
ES-MS m1z 446.0 [M+H]+, LCMS RT (min) 2.34.
Example 16 as shown in Table B was made according to this method substituting the appropriate starting materials.

Example 11 Preparation of N-(2,2-difluoro-1,3-benzodioxol-5-yl)-5-{ f(2-{ f(ethylamino) carbonyllamino}Ryridin-4- 1)~yllaminol-l-methyl- 1 H-pyrazole-4-carboxamide trifluoroacetate O \ I O~F
(J1 H
N NH H H
CH3 NuN~CH3 O iN IOI
F
OH
F F

The title compound was prepared using the same method described for Example 1.
The intermediate L was used in place of intermediate D and the concentrated HPLC
fractions were analyzed without free-basing with NaHCO3.

1H NMR (300 MHz, CD3CN) S 8.45 (s, 1H), 8.30 (s, 1H), 8.02 (d, 1H), 7.77 (s, 1H), 7.73 (s, 1H), 7.34 (s, 1H), 7.26 (d, 1H), 7.20 (d, 1H), 7.15 (d, 1H), 4.65 (s, 2H), 3.68 (s, 3H), 3.28 (q, 2H), 1.15 (t, 3H); ES-MS nz/z 474.3 [M+H]+, LCMS RT (min) 2.53.

Example 12 Preparation of N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-5-{ f (2-{f(methylarnino)carbonyllaminolpyridin-4- 1)methyllaminol-1 H-pyrazole-4-carboxamide trifluoroacetate O F
~ ~
O F
N/ H
N NH H H
CH3 t'N NuN.CH

F
OH
F F

Step 1: Preparation of ethyl5-f f(2-aminopyridin-4- 1)rnethyll(formyl)aminol-l-methyl-1 H-pyrazole-4-carb oxylate O
O---CHa N

~ ~ NH2 ~N

A solution of crude ethyl 5-(formylamino)-1-methyl-lH-pyrazole-4-carboxylate (500.00mg, 2.54mmo1) from Example 2, step 1, in THF (7.5ml) was treated with diazabicyclo(5.4.0)undec-7-ene (0.57m1, 3.80mmo1) and allowed to stir at room temperature for 30 minutes. 2-Amino-4-chloromethylpyridine (723.09mg, 5.07mmo1) was added, and the reaction mixture was heated to 60 C for one hour, then allowed to stir at room temperature for 16 h. The reaction mixture was then diluted with ethyl acetate and washed with saturated NaHCO3 solution, followed by water, then brine. The organic layer was dried over NaaSO4 and concentrated in vacuo, yielding 440mg (57.1%, impure) product as a 2:1 mixture of product to deformylated product.
ES-MS rrz/z 304.1 [M+H]+, HPLC RT (min) 1.08.
Step 2: Preparation of ethyl5-f({2-f(tert-butoxycarbonyl)aminolpyridin-4-yl 1 methyl)(formyl)aminol-l-methyl-lH-pyrazole-4-carboxylate O
O--~CH3 N
H3C N~O
N
~ N ~-O

A solution of crude ethyl5-[[(2-aminopyridin-4-yl)methyl](formyl)amino]-1-methyl-1H-pyrazole-4-carboxylate (500.OOmg, 1.651nmol) in THF (5m1) was treated with N,N-diisopropylethylamine (0.32m1, 1.81mmo1) and 4-dimethylaminopyridine (20.14mg, 0.16mmo1). Di-tert-butyl dicarbonate (1.81m1 of 1M solution in THF) was added to the reaction mixture and allowed to stir at room temperature for 16 h. The reaction mixture was then diluted with ethyl acetate and washed with concentrated NH4C1 solution, followed by water, then brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude residue was triturated with ether, and the solvent was again evaporated yielding 600mg (90.1%, impure) product. The product was used without purification.

Step 3: Preparation of 5-f({2-f (tert-butoxycarbonyl)aminolpyridin-4-l~thyl)aminol-1-methyl-1 H-pyrazole-4-carboxylic acid O
N OH
% N

/ ~ N
~N O~- O

The title compound (130.0mg, 25.1 Io) was prepared in a similar fashion to Example 2, step 3, using ethyl5-[({2-[(tert-butoxycarbonyl)amino]pyridin-4-yl}methyl)(formyl)amino]-1-methyl-lH-pyrazole-4-carboxylate (600.0mg, 1.49mmol) as starting material.

1H NMR (300 MHz, CD3CN) 8 8.28 (bs, 1H), 8.18 (d, 1H), 7.89 (s, 1H), 7.55 (d, 1H), 6.98 (m, 1H), 4.59 (m, 2H), 3.64 (s, 3H), 1.50 (s, 9H).
Step 4: Preparation of tert-butyl (4-f f(4- { f(2 2-difluoro-1 3-benzodioxol-5-yl)arninolcarbonyl l-1-methyl-lH-Ryrazol-5-yl)aminol methyl I pyridin-2-yl)carbamate O O F
N~ N ~
N H O F

NH y-'ON O~ - 0 The title compound (90.0mg, 48.4%) was prepared in a similar fashion to Example 2, step 4, using 5-[({2-[(tert-butoxycarbonyl)amino]pyridin-4-yl}methyl)amino]-1-methyl-1H-pyrazole-4-carboxylic acid (130.0mg, 0.37mmol) as starting material. This material was used without purification.
ES-MS nz/z 502.8 [M+H]+, HPLC RT (min) 2.83.

Step 5: Preparation of 5-f f(2-aminopyridin-4-yl)methyllaminoI -N-(2 2-difluoro-1 3-benzodioxol-5-yl)-1-methyl-1 H-pyrazole-4-carboxamide O ~
\ ~ F
N x N H O F

~ ~ NH2 ~N

A solution of tert-butyl (4-{ [(4-{ [(2,2-difluoro-l,3-benzodioxol-5-yl)amino]carbonyl } -1-methyl-1 H-pyrazol-5-yl)amino]methyl }pyridin-2-yl)carbamate (66.15mg, 0.13mmol) in dichloromethane (1.5m1) was treated with trifluoroacetic acid (1.4m1, 18.12mmo1) and allowed to stir at room temperature for 16 hours. The reaction mixture was then diluted with ethyl acetate and washed with 1N NaOH solution.
The aqueous layer was extracted with EtOAc, and the organic extracts were combined and dried over MgSO4. Concentration of the EtOAc solution in, vacuo gave 60.0mg (>99%) crude product estimated 50% pure by 1H NMR. The product was used without purification.
ES-MS rn/z 403.1 [M+H]+, HPLC RT (min) 0.99.

Step 6: Preparation of N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-5-{ f(2-j f (methylamino)carbonyllamino lpyridin-4-yl)meth_yllamino l-1 H-pyrazole-4-carboxarnide trifluoroacetate O \ I O 'F

O~F
N// ~ H
N NH H H
CH3 NuN.CH

F
OH
F F

The title compound was prepared using the same method described for Example 8 step 3. In Step 3, methyl isocyanate was used in place of ethyl isocyanate.
The worlcup for the final step was different in that the concentrated HPLC fractions were analyzed without free-basing with NaHCO3.

1H NMR (300 MHz, CD3CN) 812.10 (s, 1H), 8.40 (s, 1H), 8.06 (bd, 2H), 7.72 (d, 2H), 7.32 (s, 1H), 7.20-7.27 (m, 2H), 7.15 (d, 1H), 4.63 (s, 2H), 3.63 (s, 3H), 2.80 (d, 3H);
ES-MS in/z 460.3 [M+H]+, LCMS RT (min) 2.37.

Table B

LCMS
Entry Structure Chemical Name LC-MS RT
No. [M+H]+
min N
H3c-N~' '~o 1-methyl-5-{[(2-{[(methylamino)carbonyl]a HN HN O F mino}pyridin-4-N ~F yI)methyl]amino}-N-NH O F F (2,2,3,3-tetrafluoro-2,3-dihyd ro-1,4-benzodioxin-6-oNH yI)-1 H-pyrazole-4-13 H 3 c carboxamide; 532 2.63 HN HN 1-methyl-5-{[(2-\ ~ ~ {[(methylamino)carbonyl]a N / mino}pyridin-4-O yl)methyl]amino}-N-[4-NH F
(trifluoromethoxy)phenyl]-ONH F F 1 H-pyrazole-4-14 Hs6 carboxamide; 464.1 2.4 5-{[(2-HN HN {[(ethylamino)carbonyl]ami , iao no}pyridin-4-N yl)methyl]amino}-1-methyl-o~ H kF N-[4-NH F F (trifluoromethoxy)phenyl]-1 H-pyrazole-4-15 ~H3 carboxamide; 478 2.5 H30-NN~ O F
OI
HN N F F 5-[({2-H [(aminocarbonyl)amino]pyr i ~ idin-4-yI}methyl)amino]-1-N ~ methyl-N-[4-HN (trifluoromethoxy)phenyl]-> NH2 1 H-pyrazole-4-16 carboxamide; 450 2.4 O F 1-methyl-5-{[(2-N~ N o~GF {[(methylamino)carbonyl]a H H mino}pyridin-4-N NHH ~-N O yl)methyl]amino}-N-[3-H3~ 3 N (trifluoromethoxy)phenyl]-1 H-pyrazole-4-17 N carboxamide; 464 2.48 1"~F
H3C-NN~ p ~ S\
HN N F F 1-methyl-5-{[(2-H {[(methylamino)carbonyl]a N ~ mino}pyridin-4-yl)methyl]amino}-N-{4-HN H [(trifluoromethyi)thio]phen N yl}-1 H-pyrazole-4-11 18 0 CH3 carboxamide; 480.1 2.64 H3C-NN~-p I a"~z p F N-(3-chloro-2,2,3-trifluoro-F 2,3-dihydro-1,4-HN
p~
CI F benzodioxin-6-yI)-1-methyl 5-{[(2-N ~ {[(methylamino)carbonyl]a HN H mino}pyridin-4-N yl)methyl]amino}-1 H-19 p cH3 pyrazole-4-carboxamide; 526 2.73 Example 20-a Preparation of N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-5-{ [(2{methyl[(methylamino)carbonyllaminolpyridin-4-yl)methyllamino}-1H-pyrazole 4-carboxamide 0 ~ ~ ~ F
~ I N O
N
H

H3C I ~ Ny N'CH

~N 0 Step 1: Preparation of [2-(methylamino)pyridin-4-yllmethanol NH

N
A solution of (2-chloropyridine-4-yl)methanol (from the preparation of Intermediate P, Step 1) and methylamine hydrochloride in pyridine is heated at 200 C in a sealed tube for about 16 h. The solvent is removed by evaporation in vacuo and the crude product residue is purified by chromatography on silica gel using a gradient from dichloromethane to about 10 % methanol in dichloromethane.

Step 2 Preparation of 4-(chloromethyl)-N-methylpyridin-2-amine ~ NH
I ~N

By using the general method of preparation of Intermediate E, Step 1 but substituting [2-(methylamino)pyridin-4-yl]methanol for (2-aminopyridin-4-yl)methanol, the Title compound is prepared.

Step 3. Preparation of N-f4-(chloromethyl)pyridin-2-_yll-N,N'-dimeth. l tTN Ny N'CH3 O
The step is carried out using the method described for the preparation of Intermediate L but using the product of Step 2 above rather than 4-(chloromethyl)pyridin-2-amine and methyl isocyanate rather than ethyl isocyanate.

Step 4: Preparation of N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-5-{r(2-{ methyl((methylamino)carbonyll amino }pyridin-4-yl)methyllamino } -1H-p_yrazole-4-carboxamide 0 ~ ~ ~ F
N, I N O
H

H3C ~ Ny N'CH3 I
,N 0 The title compound can be prepared using the same method described for Example 1 but starting with 5-amino-N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-lH-pyrazole-4-carboxamide (Intermediate A) and a proportionate amount of N-[4-(chloromethyl)pyridin-2-yl]-N,N'-dimethylurea (from Step 3) rather than Intermediate D.
The reaction mixture is heated at 60 C in a foil wrapped flask under nitrogen for between 2 and 24 h until an LCMS analysis of the reaction mixture shows substantial conversion to products. The resulting final crude mixture is diluted with saturated aqueous sodium bicarbonate and extracted 3 times with ethyl acetate. The combined extracts are dried (Na2SO4) and evaporated in vacuo to yield a residue that is purified by preparative C18 HPLC using water to acetonitrile gradient (usually 10-50%) with added 0.05-0.1 % TFA.
The free base is prepared from the TFA salt by addition of saturated aqueous NaHCO3 to the fractions containing the product and extraction with dichloromethane followed by drying of the extract (Na2SO4) and concentration in vacuo to yield pure title compound.

Examples 20-b to 20-x O
H,Ar N% N NH H R13 H3C \ N~N,R1-6 I ~N O

Step 1: Preparation of various N-(4-(chloromethyl)p~idin-2-y11ureas with other N-substituents CI H R1-a N~N,R16 By using the methods described for the preparation of Intermediate L but substituting the appropriate alkyl or aryl isocyanate rather than ethyl isocyanate, (using either DMF or dichloromethane) the intermediates which lead to examples 20-b to 20-g, 20-i, and 20-o to 20-w of Table C are prepared. By using the methods described for the preparation of Intermediate E, step 2 but using the appropriate carbamoyl chloride rather than acetoxyacetyl chloride, the intermediates which lead to Examples 21-k to 21-n of Table C can be prepared. In all cases the appropriate isocyanate or carbamoyl chloride is either comrnercially available or the synthesis is straightforward to one skilled in the art and is reported in the general literature.

Step 2: Preparation of the Title Compounds (Table C) O
N~ I H,Ar ,N NH H Ri s H3C N-Tr N, Ri-6 The title compounds can be prepared using the same method described for Example 1 but starting with 5-amino-N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-lH-pyrazole-4-carboxainide (Intermediate A) or another material from the list of Intermediates B, B-2, B-3, B-4 or B-5 instead of hitermediate A and proportionate amounts of the appropriate Intermediate from Step 1 above rather than Intermediate D and also proportional amounts of the other reaction components. The reaction mixture is heated at 60 C in a foil wrapped flask for between 2 and 24 h until an LCMS
analysis of the reaction mixture shows substantial conversion to products. The resulting final crude mixture is diluted with saturated aqueous sodium bicarbonate and extracted 3 times with ethyl acetate. The combined extracts are dried (Na2SO4) and evaporated in vacuo to yield a residue that is purified by preparative C 18 HPLC using water to acetonitrile gradient (usually 10-50%) with added 0.05-0.1 % TFA. The free base is prepared from the TFA
salt by addition of saturated aqueous NaHCO3 to the fractions containing the product and extraction with dichloromethane followed by drying of the extract (Na2SO4) and concentration in vacuo to yield pure title compound. In the case of Title compounds 20-h and 20-j, the initial blocked products 20-g and 20-i respectively are converted to the final Title compounds by treatment with potassium carbonate in methanol or ethanol.
Structures and names of the Title Compounds 20-a to 20-x are shown in Table C

Table C
Example Structure Name Number 20-a O CC ~F N-(2,2-difluoro-1,3-benzodioxol-5-1 -1-meth 1-5- 2-0 Y ) Y { [( N N I H {methyl[(methylamino)carbonyl]a , N H CH3 H
H3C rN.CH mino}pyridin-4-yl)methyl]amino}-N 0 1H-pyrazole-4-carboxamide 20-b , O F 1-methyl-5-{ [(2-{ [(pyridin-4-0 ~ ~
Nr I N~ O F ylamino)carbonyl]amino}pyridin-H F 4-yl)methyl]amino}-N-(2,2,3,3-N NH
H3C Nu H tetrafluoro-2,3-dihydro-1,4-N 0 N benzodioxin-6-yl)-1H-pyrazole-4-\ II
carboxamide 20-c O OF 1-methyl-N-(2,2,4,4-tetrafluoro-0 4H-1,3-benzodioxin-6-yl)-N H F F 5-{[(2-{[(1,3-thiazol-2-N NH
H3C H N S ylamino)carbonyl]amino}pyridin-N O N~ 4-yl)methyl] amino }-1 H-pyrazole-4-carboxamide 20-d O , O~F 5-({[2-({[(4-cyano-2-methyl-l,3-~ ~ F oxazol5-N ( , H N yl)amino]carbonyl}amino)pyridin-N NH t H H
H3C N N 4-yl]methyl}amino)-1-methyl-N-N O O i N [4-(trifluoromethoxy)phenyl]-1H-~ H3 pyrazole-4-carboxamide s0 20-e 0 F 5-{ [(2-F
N i I N O~ F {[(cyclopropylamino)carbonyl] ami N H no}pyridin-4-, NH H H
Hsc Ny N yl)methyl]amino}-1-methyl-N-[3-N O (trifluoromethoxy)phenyl]-1 H-pyrazole-4-carboxamide 20-f 0 vF N-(2,2-difluoro-1,3-benzodioxol-5-F
1 -1-meth 1-5- 2-O Y) Y {[( N
N,N NH H H {[(pyrimidin-2-HsC Ny N'Ti" N\ ylamino)carbonyl] amino } pyridin-N 0 N J 4-yl) methyl] amino } -1 H-pyrazole-4-carboxamide 20-g 0 O F 5-{[(2-~ ~F {[(benzoylamino)carbonyl]amino}
Ni N O
H F pyridin-4-yl)methyl] amino }-1-N NH /
H3C N N ~ ~ methyl-N-(2,2,3,3-tetrafluoro-2,3-~
I N O O dihydro-1,4-benzodioxin-6-yl)-1H-pyrazole-4-carboxamide e 20-h O , O F 5-[({2-~ ~ ~F [(aminocarbonyl)amino]pyridin-4-N/ ~ H O F yl } methyl)amino]-N NH H
H3C NuNH2 1-methyl-N=(2,2,3,3-tetrafluoro-II
I ~ N O 2,3-dihydro 1,4 benzodioxin 6-yl)-1 H-pyrazole-4-carboxamide 20-i o I 0~F 2-[({ [4-({ [1-methyl-4-({ [4-~ F (trifluoromethoxy)phenyl]
N~ x N O
N H amino}carbonyl)-1H-pyrazol-5-N J yl] amino } methyl)pyridin-2-~N 0 yl]amino}carbonyl)amino]ethyl acetate 20-j o , pF 5-({ [2-({ [(2-~ I F hydroxyethyl)amino]carbonyl}ami N N ~ H no)pyridin-4-, NH H H OH
H3C N N J yl]inethyl}amino)-1-methyl-N-[4-~ ~ N ~ (trifluoromethoxy)phenyl]-1 H-pyrazole-4-carboxamide 20-k 0 F F 5- {[(2-N~ I H F {[(dirnethylamino)carbonyl] amino }
N NH H CH3 pyridin-4-yl) H3C ~ N y N. CH3 methyl]amino}-1-methyl-N-[3-I ~ N 0 (trifluoromethoxy)phenyl]-1H-pyrazole-4-carboxamide 20-1 0 \ I O ~ F 5-( {[2-( {[(2-chloropyridin-3-N O/~ yl)(methyl)amino]carbonyl}amino) N% I H
N NH H CH3 CI pyridin-4-yl]methyl}amino)-N-H3C N~ N N (2,2-difluoro-1,3-benzodioxol-~ N 0 i 5-yl)-1-methyl-lH-pyrazole-4-carboxamide O F 4-methyl-N-(4-{ [(1-methyl-4-20-m O a-, { [(2,2,3,3-tetrafluoro-2,3-dihydro-~F
N~ ~ H O F
1,4-benzodioxin-6-IN NH H r'N.CH3 H3C N N J yl)amino]carbonyl}-1H-pyrazol-5-N O yl)amino]methyl}pyridin-2-yl)piperazine-l-carboxamide N-(4-{ [(I-methyl-4-1[(2,2,4,4-Oj 20-n O ic, N 0 tetrafluoro-4H-1,3-benzodioxin-N/ ~ H F F 6-yl)amino]carbonyl}-1H-pyrazol-N NH H r'O
H3C N N J 5-yl)arnino]methyl}pyridin-C,, N O 2-yl)morpholine-4-carboxamide 20-o O , Of ',F 1-methyl-5-{ [(2-~ ~ 0 {[(methylamino)carbonyl]amino}p N~ N
~ H F F yridin-4-N NH
H3C N N yl)methyl]amino}-N-(2,2,4,4-~ CH3 N y tetrafluoro-4H-1,3-benzodioxin-6-yl)-1 H-pyrazole-4-carboxamide 1-methyl-5-{ [(2-O
20-p 0 J:Dr F {[(methylamino)carbonyl]amino}p N~ N
, ~ H yridin-4-N
NH
H
H3C N N,CH yl)methyl]amino}-N-[4-~ N ~ 3 (trifluoromethoxy)phenyl]-1H-pyrazole-4-carboxamide 20-q p ao F /F 1-methyl-5-{[(2-N r N =~F {[(methylamino)carbonyl]arnino }p 'N NH H H yridin-4-HsC NyN-CH3 yl)methyl]amino}-N-[3-N O (trifluoromethoxy)phenyl]-1H-pyrazole-4-carboxam.ide O F N-(2,2-difluoro-1,3-benzodioxol-5-20-r 0 J::)c Nr HO F yl)-1-methyl-5 {[(2-{[(pyridin-H3C I~ NN I~N ylamino)carbonyl]aznino}pyridin-~ N O 4-y1)methyl]amino}-1H-pyrazole-4-carboxamide 20-s O F
5-({[2-({[(2-furylmethyl) ~F amino]carbonyl } amino)pyridin-4-Nr I N F
~N H yl]methyl } amino)-1-methyl-N-, H3C NH H N ~ ~ (2,2,3,3-tetrafluoro-2,3-dihydro-~
( N N 0 1,4-benzodioxin-6-y1)-1H-pyrazole-4-carboxamide 20-t 0 JIj1_O<F 1-methyl-5-({ [2-({ [(pyridin-4-F ylmefihyl)amino]carbonyl}amino) N
t'N NH H H IN pyridin-4-yl]methyl}amino)-N-[4-H3C N N (trifluoromethoxY)PhenY1]-I ~ N O~' ~ O 1H-pyrazole-4-carboxamide 20-u O ~ F N-(2,2-difluoro-l,3-benzodioxol-5-~ 1 -1-meth 1-5- 2-~ I N O
N% Y) Y ({L
H ({ [(pyridin-2-N NH H H N- H3C N N ~ I ylmethyl)amino]carbonyl}amino)p N 0 yridin-4-yl]methyl } amino)-1H-pyrazole-4-carboxanude 20-v O o ~F YN-(2,2-difluoro-1,3-benzodioxol-5-j::) 1)-1-methY1-5-({[2-N'N I N NH H H O ({ [(tetrahydrofuran-2-HsC N y N ylmethyl)amino]carbonyl } amino)p N 0 yridin-4-yl] methyl } amino)-1 H-pyrazole-4-carboxamide 20-w o , o F 1 -methyl-5-({ [2-({ [(2-pyridin-2-~ I ~F ylethyl)amino]carbonyl}amino) N N o F
N H H H pyridin-4-yl]inethyl } amino)-N-NH
H3C ~ NuN N\ (2,2,3,3-tetrafluoro-2,3-dihydro-I~ N IOI 1,4-benzodioxin-6-yl)-1H-pyrazole-4-carboxamide 20-x 0 JSF 1-methyl-5-{ [(2-~ F {[(methylamino)carbonyl]amino}p Ni N
H yridin-4-N NH
H3C N N,CH yl)methyl]amino}-N-{4-~ N ~ 3 [(trifluoromethyl)thio]phenyl}-1H-pyrazole-4-carboxamide Example 21 Preparation of N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-meth.yl-5-({[2-(methylamino)pyrimidin-4-yllmethyllamino)-1H-pyrazole-4-carboxamide 0 \ ~ XF
N~ I N O
H
N NH H
CH3 N~N, CH

oN

Step 1. Preparation of 5-{f(2 6-dichloropyrimidin-4-yl)methyllamino}-N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-meth 1-1H-pyrazole-4-carboxamide XF
0 \ J::DCO
N~ I N , H
N NH
HsC NCI
oN
CI
A mixture of 2,4-dichloro-6-(chloromethyl)pyrimidine (Intermediate 0, 99 mg, 0.5 mmol) and sodium iodide (75 mg, 0.5 mmol) in anhydrous DMF (0.5 mL) is stirred under nitrogen until a solution forms and then 5-amino-N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-lH-pyrazole-4-carboxamide (Intermediate A, 100 mg, 0.33 nrnmol) is added. The resulting mixture is heated and stirred under nitrogen at 40 C for 4 h and then at 59 C
overnight. If after TLC analysis some remaining pyrazole starting materials are present, additional 2,4-dichloro-6-(chloromethyl)pyrimidine (30 mg) is added and the reaction rnixture is again heated at 59 C for another 2 h. The resulting final crude mixture is diluted with saturated aqueous sodium bicarbonate and extracted 3 times with ethyl acetate. The combined extracts is dried (Na2S04) and evaporated in vacuo to yield a residue that is purified by chromatography on silica gel using a gradient from 10-40 %
ethyl acetate in hexane.
Step 2. Preparation of 5-( { f 6-chloro-2-(methylamino)pyrimidin-4-yllmethyl I
amino)-N-(2 2-difluoro-1 3-benzodioxol-5-yl)-1-methyl-lH-pyrazole-4-carboxamide and 5-({ f2-chloro-6-(methylamino)pyrimidin-4- ll~methyl}amino)-N-(2 2-difluoro-1 3-benzodioxol-5-yl)-1-meth 1-1H-pyrazole-4-carboxamide O \ o~~ p o,F
OJ~ ~O~ F
H H
N NH H N NH
CH3 NN,CH3 CH3 I N~CI
iN ~N

A solution of 5-{[(2,6-dichloropyrimidin-4-yl)methyl]amino}-N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-lH-pyrazole-4-carboxamide (the product of step 1, 0.2 minol) and methylamine (0.4 mmol) in methanol (1.2 mL) can be stirred in a sealed tube for -5h. The products can be purified by direct injection on a preparative HPLC to yield purified isomers wherein the 6-(methylamino)pyrimidin-4-yl isomer is expected to be the major product.
Step 3. Preparation of the Title Compound A mixture of 5-( {[6-chloro-2-(methylamino)pyrimidin-4-yl]methyl } amino)-N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-lH-pyrazole-4-carboxamide (the minor product of step 2, 0.18 mmol) plus palladium (II) hydroxide (0.36 mmol) and ammonium formate (1.76 mmol) in ethyl acetate (15 mL) and methanol (15 mL) can be stirred with heating at reflux for 16 h. The product solution can be filtered using Celite0 filter aid and evaporated in vacuo. The residue can be purified by preparative C 18 HPLC
using a gradient from 5 to 45% acetonitrile in water plus 0.1% TFA. Evaporation of product containing fractions can yield pure compounds as TFA salts. Alternatively, the fractions containing the product can be mixed with saturated aqueous NaHCO3 and extracted with dichloromethane. The extracts are dried (Na2SO4) and evaporated in vacuo to yield pure free base title compound.

Example 22 Preparation of 5-{[(2-aminopyridin-4-vl)methyllamino}-1-methyl-N-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-1H-pyrazole-4-carboxamide O O F F
IF
N/ ~ H O F
N NH
CH3 ~ NH2 I ~N

This compound was prepared as shown in Example 8 and is the product of Step 2.
Example 23 Preparation of tert-butyl (4-jr(4-{ f (2,2-difluoro-1,3-benzodioxol-5-yl)aminolcarbonyll-l-methyl-lH-p_yrazol-5-yl)aminol methyllpyridin-2-_yl)carbamate F
N~ N x ,N ~ H O F

~ ~ NH
~ N O~--0 This compound was prepared as shown in Example 12 and is the product of Step 4.
Example 24 Preparation of 5-{ f (2-aminopyridin-4-yl)methyllaminol-N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-lH-pyrazole-4-carboxamide O O
F
N ~ A

~ ~ NH2 ~N
This compound was prepared as shown in Example 12 and is the product of Step 5.

B. Evaluation of physiological activity The utility of the compounds of the present invention can be illustrated, for example, by their activity in the P-AKT/PKB Cytoblot Assay described below.
The involvement of the P-AKT/PKB[ PI3K/AKt] pathway as a target for cancer chemotherapy has been recognized in the art. For example, see F. Chang et al, Iizvolvement of PI3K1Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation:
a target for carzcer chem,otherapy, Leukemia, 2003, 17: p. 590-603; K. A. West et al, Activation of the PI3K/Akt pathway and chemotlzerapeutic resistance, Drug Resistance Updates, 2002, 5: p. 234-248; and P. Sen et al, Involvefnent of the Akt/PKB
signaling pathway with disease processes, Molecular and Cellular Biochemistry, 2003, 253: p. 241-246.

P-AKT/PKB Cytoblot Assay Protocol with H209 Cells H209 small cell lung carcinoma cells in log phase were plated at 50,000 cells/well in 96-well poly-lysine coated, clear bottom/ black-sided plates (Becton-Dickinson, USA Cat #
354640) in 100 l RPMI medium containing 0.1% (w/v) BSA, and incubated overnight at 37 C in 5% CO2 incubator. The following day, compounds (10 mM stock solutions in DMSO) were added to the plates to generate final concentrations of 0.0, 0.01, 0.03, 0.1, 0.3, 1.0, 3.0 and 10 M for IC50 determinations and incubated for 1 hour at 37 C. Cells were then left untreated or stimulated with Stem Cell Factor (SCF: Biosource Cat #
PHC2116) at a final concentration of 25 ng/mL for 5 minutes at 37 C in 5% CO2 incubator. The media was then removed using a vacuum manifold and the cells were washed once with Tris Buffered Saline (TBS). Cells were then fixed by adding 200 l of cold 3.7% (v/v) formaldehyde in TBS to each well for 15 minutes at 4 C. After removal of the formaldehyde, the cells were treated with the addition of 50 l of methanol (at -20 C) to each well for 5 minutes. After removal of the methanol, 200 l of 1%
(w/v) BSA
in TBS was added to each well to block non-specific antibody binding sites and the plate was incubated at room temperature for 30 minutes.
After removal of the blocking buffer, 50 1 of p-(S473) AKT rabbit polyclonal antibody (Cell Signaling, USA Cat # 9277S) was added at a dilution of 1:250 in 0.1%
(w/v) BSA in TBS, and the plate was incubated at room temperature for 1 hour.
Plates were then washed 3 times with cold TBS containing 0.05% (v/v) Tween 20 (TBS-T) and 100 l of Horseradish peroxidase (HRP)-conjugated goat-anti-rabbit antibody (Amersham, USA Cat # NA934V) at a dilution of 1:250 in TBS-T was added and the plate was incubated at room temperature for lh. After washing with ice-cold TBS-T four times, 100 l of Enhanced Chemiluminescence (ECL) reagent (Amersham, USA Cat# RPN2209) was added to each well and mixed on a mini-orbital shaker for 1 min. The plate was then read on a Perkin Elmer Victor 5 Multilabel Counter (#1420-0421).
Compounds of examples 1, 3-a, 3-b, 3-c, 3-d, 8, 9, 10,11, 12, 13, 14, 15, 16, 16, 17, 18, 19.
were tested in the above P-AKT/PKB Cytoblot assay, with the result that these examples exhibited IC50 values of less than 500 nM. In one embodiment, the present invention relates to a compound which exhibits an IC50 value of less than 500 nM in this assay.

The utility of the compounds of the present invention can also be illustrated, for example, by their activity in the phosph-ERK Assay described below.
Growth-factor induction of the RAS/MEK/ERK signaling pathway leads to the induction of phosphorylation of a number of proteins including phospho-ERK (See C. J.
Marshall, MAP kinase kinase kinase, MAP kinase kinase and MAP kinase, Current Opinions in Genetic Development, 1994, 4: p. 82-89). The importance of this pathway in cancer biology has been recognized in the art. Activation of the RAS signaling pathway is an important mechanism by which cancer develops (R. Herrera, et al, Unr aveling the conaplexities of the Raf/MAP kinase pathway for pharmacological intervetztion, Trends Mol. Med., 2002, 8: p. S27-3 1). Mutational activation of RAS or downstream effectors as well as growth factor induction of this pathway leads to increased tumor cell proliferation and survival (A. A. Adjei, Blockifzg oncogenic RAS sigyzaling for cancet=
therapy, J. Natl.
Cancer Inst., 2001, 93(14): p. 1062-1074; J Schlessinger, Cell signaling by receptor tyrosine kinases, Cell, 2000, 103: p. 211-225).

Phospho-ERK Cytoblot Assay Protocol with MDA-MB 231 Cells MDA-MB-231 cells in log phase were plated at 25,000 cells/well in 96-well opaque plates (Falcon, USA Cat # 353296) in 100 L RPMI medium containing 10% (w/v) FBS, and incubated overnight at 37 C in 5% CO2 incubator. The following day, the growth medium was removed from the plate by aspiration and replaced with RPMI medium containing 0.1% BSA and example compounds diluted to generate final concentrations of 0.0, 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1 and 3 M. Cells were incubated with compound for 1 hour at 37 C in a 5% CO2 incubator. The media was then removed from the plate by aspiration and the cells were washed once with 180 ,L/well cold Tris Buffered Saline (TBS). After removal of the wash buffer, the cells were fixed by adding 180 L of cold 3.7%
(v/v) formaldehyde in TBS to each well for 1 hour at 4 C. After removal of the formaldehyde, the cells were treated with the addition of 60 L of -20 C methanol to each well for 5 ininutes at 4 C. The methanol was removed and the cells were washed with 180 L/well of 5% (w/v) BSA in TBS. To block non-specific antibody binding sites, each well was treated with 180 L/well 5% BSA (w/v) in TBS for thirty minutes at room temperature.
After removal of the blocking buffer, 50 L of an anti-phospho-p44/42 MAP
kinase (Thr202/Tyr204) rabbit polyclonal antibody (Cell Signaling, USA Cat # 9101) was added to each well at a dilution of 1:1000 in 5% (w/v) BSA in TBS, and the plate was incubated at 4 C overnight. Plates were then washed three times with 300 L/well TBS at room temperature. The plates were then incubated with 50 gL of Horseradish peroxidase (HRP)-conjugated goat-anti-rabbit antibody (Amersham, USA Cat. # NA934V) at a dilution of 1:1000 in 5% BSA-TBS at room temperature for 1 hr. After washing the plate three times with 300 L/well TBS, 60 L of Enhanced Chemiluminescence (ECL) reagent (Amersham, USA Cat# RPN2209) was added to each well and incubated at room temperature for five minutes. The plate was then read on a Perkin Elmer Victor Multilabel Counter (#1420-0421).
The compounds of examples 1, 10, 11, 12, 13, 14, 15, 17, 18, 19, were tested and showed an IC50 value of less than 3 M in this assay. In one embodiment, the present invention relates to a compound which exhibits an IC50 value of less than 3 M.

The utility of the compounds of the present invention can also be illustrated, for example, by their activity in the flk-1(murine VEGFR2) Assay described below.
The VEGF-VEGFR2 signaling pathway has been extensively characterized as an important regulator of angiogenesis and tumor angiogeneisis (See G.
Yancopoulos et al, Vascula.r-specific growth factors afid blood vessel forizzatiofz, Nature, 2000, 407: p.. 242-248; D. Shweiki et al, Ifzductiofz of vascular efidotl2elial growth factor expression by lzypoxia afzd by glucose deficiezzcy ifzinulticell spheroids: Ifzzplicatioyzs for tufnor=

angiogenesis, Proc. Natl. Acad. Sci, 1995, 92: p. 768-772). Inhibition of tumor cell growth by blocking this pathway has been well documented in the art. Administration of soluble VEGFR2 receptors inhibits the growth of a wide variety of tumors (See C. Bruns et al, Vascular endothelial growt7a factor is an in vivo survival factor for tumor endotlieliunz in a murine ntodel of colorectal liver metastases, Cancer, 2000, 89: p. 495-499; B.
Millauer et al, Glioblastoina growtlz inhibited in vivo by a dominant-negative FLK-1 mutant, Nature, 1994, 367: p. 576-579). Neutralizing antibodies to VEGF or VEGFR2 and VEGF
antisense suppress tumor growth in vivo (See K. Kim et al, Inhibition of vascular endotlteli.al growth factor-induced angiogenest's suppresses tumor growtlz in vivo, Nature, 1993, 362: p. 841-844; M. Prewett et al, Antivascular erzdothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody iithibits tuntor angiogenesis and growth of several mouse and human tutnors, Cancer Research, 1999, 59: p. 5209-5218; M.
Saleh et al, Inhibition of growth of C6 glioma cells in- vivo by expression of antisense vascular endotlzelial growth factor sequence, Cancer Research, 1996, 56: p. 393-401).

Flk-1 (murine VEGFR-2) Biochemical AssaX
This assay was performed in 96-well opaque plates (Costar, USA Cat #3915) in the TR-FRET format. Reaction conditions were as follows: 10 M ATP, 25 nM poly (Glu,Tyr)-biotin (CIS BIO International, USA Cat#61GTOBLD), 2 nM Eu-labelled phospho-Tyr Ab (Perkin Elmer, USA Cat#AD0067), 10 nM Strepavidin-APC (Perkin Elmer, USA
Cat#CR 130-100), 7 nM Flk-1 (kinase domain), 1% DMSO, 50 mM HEPES pH 7.5, 10 mM MgC12, 0.1 mM EDTA, 0.015% BRIJ, 0.1 mg/mL BSA, 0.1% mercapto-ethanol.
Prior to the addition of enzyme, compounds were added to final concentrations ranging from 10 M to 4.56 nM in 1% DMSO. The reaction was initiated upon addition of enzyme. Final reaction volume in each well was 100 L. Time-resolved fluorescence was read after excitation at 340 nM. Emission readings were taken at both 665 and 615 nM on a Perkin Elmer Victor V Multilabel counter at 1.5 - 2.0 hrs after reaction initiation. Signal was calculated as follows: Emission 665 nm/ Emission 615 nM x 10000 for each well.

The compounds of examples 10,13, 16, 17, 18, 19, were tested and showed an IC50 value of less than 500 nM in this assay. In one embodiment, the present invention relates to a compound which exhibits an IC50 value of less than 500 nM.

Method of Treating Another embodiment of the present invention thus relates to a method of using the compounds described above, including salts thereof and corresponding compositions thereof, as cancer chemotherapeutic agents . This method comprises administering to a patient an amount of a compound of this invention, or a pharmaceutically acceptable salt thereof, which is effective to treat the patient's cancer. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for a particular cancer.
Cancers include but are not limited to solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukemias.
Examples of breast cancer include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
Examples of cancers of the respiratory tract include, but are not limited to small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
Examples of brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer. Tuinors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, and urethral cancers.
Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
Head-and-neck cancers include, but are not limited to laryngeal /
hypopharyngeal /
nasopharyngeal / oropharyngeal cancer, and lip and oral cavity cancer.
Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
These disorders have been well characterized in humans, but also exist with a similar etiology in other mainmals, and can be treated by administering pharmaceutical compositions of the present invention.

The compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. For example, the compounds of this invention can be combined with known anti-hyper-proliferative, chemotherapeutic, or other indication agents, and the like, as well as with admixtures and combinations thereof.
Optional anti-hyper-proliferative agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 1 lth Edition of the Merck Index, (1996), such as cisplatin.
Other anti-hyper-proliferative agents suitable for use with this invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilnz.an.'s The Phaf=nzacological Basis of Tlzerapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 1225-1287, (1996) such as idarubicin.

C. Operative examples relating to pharmaceutical compositions The active compound can act systemically, locally or both. For this purpose it can be administered in a suitable manner, such as for example by oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or aural administration or in the form of an implant or stent. The active compound can be administered in forms suitable for these modes of administration.

Suitable forms of oral administration are those according to the prior art which function by releasing the active compound rapidly or in a modified or controlled manner and which contain the active coinpound in a crystalline, amorphous, or dissolved form, for example tablets (which can be uncoated or coated, for example with enteric coatings or coatings which dissolve after a delay in time or insoluble coatings which control the release of the active compound), tablets or films (wafers), which disintegrate rapidly in the oral cavity, films/lyophilisates, capsules (e.g. hard or soft gelatin capsules), dragees, pellets, powders, emulsions, suspensions and solutions. An overview of application forms is given in Remington's Pharmaceutical Sciences, 18th ed. 1990, Mack Publishing Group, Enolo.

Parenteral administration can be carried out by avoiding an absorption step (e.g. by intravenous, intraarterial, intracardial, intraspinal or intralumbar administration) or by including absoiption (e.g. by intramuscular, subcutaneous, intracutaneous or intraperitoneal administration). Suitable parenteral administration forms are for example injection and infusion formulations in the form of solutions, suspensions, einulsions, lyophilisates and sterile powders. Such parenteral pharmaceutical compositions are described in Part 8, Chapter 84 of Remington's Pharmaceutical Sciences, 18th ed. 1990, Mack Publishing Group, Enolo.

Suitable forms of administration for the other modes of administration are for example inhalation devices (such as for example powder inhalers, nebulizers), nasal drops, solutions and sprays; tablets or films/wafers for lingual, sublingual or buccal administration or capsules, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions or shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems, milky lotions, pastes, foams, dusting powders, implants or stents.

The active compounds can be converted into the abovementioned forms of administration in a manner known to the skilled man and in accordance with the prior art using inert, non-toxic, pharmaceutically suitable auxiliaries. The latter include for example excipients (e.g. microcrystalline cellulose, lactose, mannitol, etc.), solvents (e.g.
liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (e.g. sodium dodecyl sulfate, polyoxysorbitan oleate etc.), binders (e.g. polyvinyl pyrrolidone), synthetic and/or natural polymers (e.g. albumin), stabilizers (e.g.
antioxidants, such as, for example, ascorbic acid), dyes (e.g. inorganic pigments such as iron oxides) or taste-and/or odour-corrective agents.

The total amount of the active ingredient to be administered will generally range from about 0.01 mg/kg to about 200 mg/kg, and preferably from about 0.1 mg/kg to about 20 mg/kg body weight per day. A unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day.
The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The daily oral dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.

It may however be necessary to deviate from the abovementioned quantities, depending on the body weight, mode of administration, the individual patient response to the active compound, the type of preparation and the time or interval of administration.

If used as active compounds, the compounds according to the invention are preferably isolated in more or less pure form, that is more or less free from residues from the synthetic procedure. The degree of purity can be determined by methods known to the chemist or pharmacist (see Remington's Pharmaceutical Sciences, 18t" ed. 1990, Mack Publishing Group, Enolo). Preferably the compounds are greater than 99% pure (w/w), while purities of greater than 95%, 90% or 85% can be employed if necessary.

The compounds according to the invention can be converted into pharmaceutical preparations as follows:

Tablet:
Composition:
100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50 mg of maize starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.
Tablet weight 212 mg, diameter 8 mm, curvature radius 12 mm.
Preparation:

The mixture of active component, lactose and starch is granulated with a 5%
solution (m/m) of the PVP in water. After drying, the granules are mixed with magnesium stearate for 5 min. This mixture is moulded using a customary tablet press (tablet format, see above). The moulding force applied is typically 15 kN.

Orally administrable suspension:
Composition:

1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mg of Rhodigel (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.
A single dose of 100 mg of the compound according to the invention is provided by 10 ml of oral suspension.

Preparation:
The Rhodigel is suspended in ethanol and the active component is added to the suspension. The water is added with-stirring. Stirring is continued for about 6h until the swelling of the Rhodigel is complete.

It is believed that one skilled in the art, using the preceding information, can utilize the present invention to its fullest extent. It should be apparent to one of ordinary skill in the art that changes and modifications can be made to this invention without departing from the spirit or scope of the invention as it is set forth herein. Other embodiments of the invention will be apparent to the skilled in the art from a consideration of this specification or practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the invention being indicated by the following claims.

Claims

1. A compound of formula (I) wherein Ar is selected from the group consisting of X is CH or N;
R1 is selected from the group consisting of H, halogen, wherein R1-2 is selected from the group consisting of .cndot. H, .cndot. (C1-C4)alkoxy, .cndot. (C1-C4)alkyl, wherein said (C1-C4)alkyl can be substituted with 0, 1, or 2 groups independently selected from - hydroxy, - (C1-C4)alkylamino, - (C1-C4)acyloxy, - (Cl-C4)alkoxy, and - (C2-C4)alkoxy substituted with 0,1 or 2(C1-C4)alkoxy groups, - wherein said (C1-C4)alkyl is independently optionally substituted with F up to the perfluoro level, .cndot. 5- or 6-membered heteroaryl, or .cndot. phenyl substituted with 0, 1, or 2 groups independently selected from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano;

R1-3 is H or (C1-C4)alkyl;
R1-4, R1-5 and R1-6 are independently selected from the group consisting of .cndot. H, .cndot. indan-5-yl, .cndot. phenyl substituted with 0, 1, or 2 groups independently selected from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano, .cndot. 5- or 6-membered heteroaryl substituted with 0,1 or 2 groups selected from - cyano, - halo, - nitro, - (C1-C4)alkyl, wherein said (C1-C4)alkyl is optionally substituted with 0, 1, or 2 groups selected from (C1-C4)alkylamino, (C1-C4)acyloxy, (C1-C4)alkoxy, and (C2-C4)alkoxy substituted with up to 0, 1 or 2 (C1-C4)alkoxy groups, .cndot. (C3-C6)cycloalkyl substituted with 0,1 or 2 groups selected from (C1-C4)alkyl, (C1-C4)alkoxy, cyano, and halo, and .cndot. (C1-C6)alkyl, wherein said (C1-C6)alkyl is independently substituted with 0 or 1 group selected from - NH2, - (C1-C4)alkoxy, - (C2-C4)alkoxy independently substituted with 0,1, 2 or 3 (C1-C4)alkoxy and OH groups, and independently optionally substituted with fluorine up to the perfluoro level, - carboxyl, - (C1-C4)alkoxycarbonyl - (C1-C4)alkylamino, - aminocarbonyl, - (C1-C4)alkylsulfonyl, - phenyl substituted with 0, 1, or 2 groups independently selected from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano, - 5- or 6-membered heteroaryl independently substituted with 0, 1, 2 or 3 groups selected from (C1-C4)alkyl, (C1-C4)alkoxy, cyano, halo, and nitro and - heterocyclyl independently substituted with 0, 1, 2 or 3 groups selected from (C1-C4)alkyl, (C1-C4)alkoxy, cyano, and halo, - and wherein said (C1-C6)alkyl is independently substituted with 0, 1 or 2 OH or halo groups, - and wherein said (C1-C6)alkyl is independently optionally substituted with F up to the perfluoro level;
and R1-3 and R1-4, R1-3 and R1-5, and R1-3 and R1-6, when attached to the same nitrogen atom, may form, together with the N atom to which they are attached, a 5- or 6-membered saturated heterocyclic ring selected from pyrrolidinyl, morpholinyl, thiomorpholinyl and piperizinyl optionally substituted on N with (C1-C4)alkyl;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein Ar is selected from the group consisting of X is CH or N;

R1 is selected from the group consisting of wherein R1-2 is selected from the group consisting of .cndot. (C1-C4)alkyl, wherein said (C1-C4)alkyl is substituted with 1 or 2 groups independently selected from - hydroxy, - (C1-C4)alkylamino, - (C1-C4)acyloxy, - (C1-C4)alkoxy, and - (C2-C4)alkoxy substituted with 0,1 or 2 (C1-C4)alkoxy groups, - wherein said (C1-C4)alkyl is independently optionally substituted with F up to the perfluoro level, .cndot. 5- or 6-membered heteroaryl, or .cndot. phenyl substituted with 1 or 2 groups independently selected from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano;
R1-3 is H or (C1-C4)alkyl;
R1-4 and R1-5 are independently selected from the group consisting of .cndot. indan-5-yl, .cndot. phenyl substituted with 1 or 2 groups independently selected from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano, .cndot. 5- or 6-membered heteroaryl substituted with 1 or 2 groups selected from - cyano, - halo, - nitro, - (C1-C4)alkyl, wherein said (C1-C4)alkyl is optionally substituted with 0, 1, or 2 groups selected from (C1-C4)alkylamino, (C1-C4)acyloxy, (C1-C4)alkoxy, and (C2-C4)alkoxy substituted with up to 0, 1 or 2 (C1-C4)alkoxy groups, .cndot. (C3-C6)cycloalkyl substituted with 1 or 2 groups selected from (C1-C4)alkyl, (C1-C4)alkoxy, cyano, and halo, and .cndot. (C1-C6)alkyl, wherein said (C1-C6)alkyl is independently substituted with 1 group selected from - NH2, - (C1-C4)alkoxy, - (C2-C4)alkoxy independently substituted with 0,1, 2 or 3 (C1-C4)alkoxy and OH groups, and independently optionally substituted with fluorine up to the perfluoro level, - carboxyl, - (C1-C4)alkoxycarbonyl - (C1-C4)alkylamino, - aminocarbonyl, - (C1-C4)alkylsulfonyl, - phenyl substituted with 0, 1, or 2 groups independently selected from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano, - 5- or 6-membered heteroaryl independently substituted with 0, 1, 2 or 3 groups selected from (C1-C4)alkyl, (C1-C4)alkoxy, cyano, halo, and nitro and - heterocyclyl independently substituted with 0, 1, 2 or 3 groups selected from (C1-C4)alkyl, (C1-C4)alkoxy, cyano, and halo, - and wherein said (C1-C6)alkyl is independently substituted with 0, 1 or 2 OH or halo groups, - and wherein said (C1-C6)alkyl is independently optionally substituted with F up to the perfluoro level;
R1-6 is selected from the group consisting of .cndot. H
.cndot. indan-5-yl, .cndot. phenyl substituted with 0, 1, or 2 groups independently selected from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano, .cndot. 5- or 6-membered heteroaryl substituted with 0,1 or 2 groups selected from - cyano, - halo, - nitro, - (C1-C4)alkyl, wherein said (C1-C4)alkyl is optionally substituted with 0, 1, or 2 groups selected from (C1-C4)alkylamino, (C1-C4)acyloxy, (C1-C4)alkoxy, and (C2-C4)alkoxy substituted with up to 0, 1 or 2 (C1-C4)alkoxy groups, .cndot. (C3-C6)cycloalkyl substituted with 0,1 or 2 groups selected from (C1-C4)alkyl, (C1-C4)alkoxy, cyano, and halo, and .cndot. (C1-C6)alkyl, wherein said (C1-C6)alkyl is independently substituted with 0 or 1 group selected from - NH2, - (C1-C4)alkoxy, - (C2-C4)alkoxy independently substituted with 0,1, 2 or 3 (C1-C4)alkoxy and OH groups, and independently optionally substituted with fluorine up to the perfluoro level, - carboxyl, - (C1-C4)alkoxycarbonyl - (C1-C4)alkylamino, - aminocarbonyl, - (C1-C4)alkylsulfonyl, - phenyl substituted with 0, 1, or 2 groups independently selected from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano, - 5- or 6-membered heteroaryl independently substituted with 0, 1, 2 or 3 groups selected from (C1-C4)alkyl, (C1-C4)alkoxy, cyano, halo, and nitro and - heterocyclyl independently substituted with 0, 1, 2 or 3 groups selected from (C1-C4)alkyl, (C1-C4)alkoxy, cyano, and halo, - and wherein said (C1-C6)alkyl is independently substituted with 0, 1 or 2 OH or halo groups, - and wherein said (C1-C6)alkyl is independently optionally substituted with F up to the perfluoro level;
and R1-3 and R1-4, R1-3 and R1-5, and R1-3 and R1-6, when attached to the same nitrogen atom, may form, together with the N atom to which they are attached, a 5- or 6-membered saturated heterocyclic ring selected from pyrrolidinyl, morpholinyl, thiomorpholinyl and piperizinyl optionally substituted on N with (C1-C4)alkyl;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein Ar is selected from the group consisting of X is CH;
R1 is selected from the group consisting of wherein R1-3 is H or (C1-C4)alkyl, R1-5 is selected from the group consisting of indan-5-yl, phenyl substituted with 1 or 2 groups independently selected from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano, 5- or 6-membered heteroaryl substituted with 1 or 2 groups selected from cyano, halo, nitro, (C1-C4)alkyl, wherein said (C1-C4)alkyl is optionally substituted with 0, 1, or 2 groups selected from (C1-C4)alkylamino, (C1-C4)acyloxy, (C1-C4)alkoxy, and (C2-C4)alkoxy substituted with up to 0, 1 or 2 (C1-C4)alkoxy groups;
(C3-C6)cycloalkyl substituted with 1 or 2 groups selected from (C1-C4)alkyl, (C1-C4)alkoxy, cyano, and halo;

and (C1-C6)alkyl, wherein said (C1-C6)alkyl is independently substituted with 1group selected from NH2, (C1-C4)alkoxy, (C2-C4)alkoxy independently substituted with 0,1, 2 or 3 (C1-C4)alkoxy and OH groups, and independently optionally substituted with fluorine up to the perfluoro level, carboxyl, (C1-C4)alkoxycarbonyl (C1-C4)alkylamino, aminocarbonyl, (C1-C4)alkylsulfonyl, phenyl substituted with 0, 1, or 2 groups independently selected from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano, 5- or 6-membered heteroaryl independently substituted with 0, 1, 2 or 3 groups selected from (C1-C4)alkyl, (C1-C4)alkoxy, cyano, halo, and nitro and heterocyclyl is independently substituted with 0, 1, 2 or 3 groups selected from (C1-C4)alkyl, (C1-C4)alkoxy, cyano, and halo, and wherein said (C1-C6)alkyl is independently substituted with 0, 1 or 2 OH or halo groups, and wherein said (C1-C6)alkyl is independently optionally substituted with F up to the perfluoro level;

R1-6 is selected from the group consisting of H, indan-5-yl, phenyl substituted with 0, 1, or 2 groups independently selected from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano, 5- or 6-membered heteroaryl substituted with 0, 1 or 2 groups selected from cyano, halo, nitro, (C1-C4)alkyl, wherein said (C1-C4)alkyl is optionally substituted with 0, 1, or 2 groups selected from (C1-C4)alkylamino, (C1-C4)acyloxy, (C1-C4)alkoxy, and (C2-C4)alkoxy substituted with up to 0, 1 or 2(C1-C4)alkoxy groups;
(C3-C6)cycloalkyl substituted with 0,1 or 2 groups selected from (C1-C4)alkyl, (C1-C4)alkoxy, cyano, and halo;
and (C1-C6)alkyl, wherein said (C1-C6)alkyl is independently substituted with 0 or 1 group selected from NH2, (C1-C4)alkoxy, (C2-C4)alkoxy independently substituted with 0,1, 2 or 3(C1-C4)alkoxy and OH groups, and independently optionally substituted with fluorine up to the perfluoro level, carboxyl, (C1-C4)alkoxycarbonyl (C1-C4)alkylamino, aminocarbonyl, (C1-C4)alkylsulfonyl, phenyl substituted with 0, 1, or 2 groups independently selected from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano, 5- or 6-membered heteroaryl independently substituted with 0, 1, 2 or 3 groups selected from (C1-C4)alkyl, (C1-C4)alkoxy, cyano, halo, and nitro and heterocyclyl is independently substituted with 0, 1, 2 or 3 groups selected from (C1-C4)alkyl, (C1-C4)alkoxy, cyano, and halo, and wherein said (C1-C6)alkyl is independently substituted with 0, 1 or 2 OH or halo groups, and wherein said (C1-C6)alkyl is independently optionally substituted with F up to the perfluoro level;

and R1-3 and R1-5, and R1-3 and R16, when attached to the same nitrogen atom, may form, together with the N atom to which they are attached, a 5-or 6-membered saturated heterocyclic ring selected from pyrrolidinyl, morpholinyl, thiomorpholinyl and piperizinyl optionally substituted on N with (C1-C4)alkyl;
or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein Ar is selected from the group consisting of X is CH;
R1 is selected from the group consisting of and wherein R1-3 is H, R1-5 is (C1-C6)alkyl, wherein said (C1-C6)alkyl is independently substituted with 1 group selected from (C1-C4)alkoxy, (C2-C4)alkoxy independently substituted with 0,1, or 2(C1-C4)alkoxy and OH groups, and independently optionally substituted with fluorine up to the perfluoro level, and wherein said (C1-C6)alkyl is independently substituted with 0, 1 or 2 OH or halo groups, and wherein said (C1-C6)alkyl is independently optionally substituted with F up to the perfluoro level;
R1-6 is selected from the group H, and (C1-C6)alkyl, wherein said (C1-C6)alkyl is independently substituted with 0 or 1 group selected from (C1-C4)alkoxy, (C2-C4)alkoxy independently substituted with 0,1, 2 or 3(C1-C4)alkoxy and OH groups, and independently optionally substituted with fluorine up to the perfluoro level, and wherein said (C1-C6)alkyl is independently substituted with 0, 1 or 2 OH or halo groups, and wherein said (C1-C6)alkyl is independently optionally substituted with F up to the perfluoro level;

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, wherein Ar is selected from the group consisting of X is CH;
R1 is selected from the group consisting of wherein R1-3 is H, R1-6 is selected from the group H, and (C1-C6)alkyl, wherein said (C1-C6)alkyl is independently substituted with 0 or 1 group selected from (C1-C4)alkoxy, (C2-C4)alkoxy independently substituted with 0,1, 2 or 3(C1-C4)alkoxy and OH groups, and independently optionally substituted with fluorine up to the perfluoro level, and wherein said (C1-C6)alkyl is independently substituted with 0, 1 or 2 OH or halo groups, and wherein said (C1-C6)alkyl is independently optionally substituted with F up to the perfluoro level;

or a pharmaceutically acceptable salt thereof.

6. A process for making a compound of claim 1, comprising (A) reacting, with or without first hydrolizing the ester group -COOR', a compound of formula (VI) wherein X and R1 have the meaning described in claim 1, and R' is lower alkyl, with a compound of formula Ar-NH2 (VIII), wherein Ar has the meaning described in claim 1; or (B) reacting a compound of formula (IX) wherein Ar has the meaning described in claim 1, with a compound of formula (IV) wherein X and R1 have the meaning described in claim 1, and subsequently reducing the resulting compound; or (C) reacting a compound of formula (IX), wherein Ar has the meaning described in claim 1, with a compound of formula (V) wherein lg represents a leaving group; or (D) reacting a compound of formula (IIa) wherein X and R1 have the meaning described in claim 1, and R' is lower alkyl, with a compound of formula (VIII) ArNH2 (VIII), wherein Ar has the meaning described in claim 1, in the presence of (R')3Al, wherein R' is lower alkyl, or (E) first hydrolizing the ester group -COOR' of a compound of formula (IIa) as described above, and subsequently reacting the resulting compound with a compound of formula (VIII) as described above.

7. A compound of claim 1 for the treatment or prevention of disorders.

8. A pharmaceutical composition comprising the compound of claim 1.

9. The pharmaceutical composition of claim 8, additionally comprising at least one pharmaceutically acceptable carrier or excipient.

10. A pharmaceutical composition of claim 8 or 9 for the treatment or prevention of cancer.

11. A process for preparing the pharmaceutical composition of claim 9, comprising combining at least one compound according to claim 1 with at least one pharmaceutically acceptable carrier or excipient and bringing the resulting combination into a form suitable for said pharmaceutical composition.

12. A use of a compound of claim 1 for manufacturing a pharmaceutical composition for the treatment or prevention of a disease.

13. The use of claim 12, wherein the disease is cancer.

14. A method of treating a disease or condition in a mammal, comprising administering to a mammal in need thereof an effective amount of a compound of claim 1.

15. The method of claim 14, wherein the disease or condition is cancer.