WO2008150446A1

WO2008150446A1 - Inhibitors of protein kinases

Info

Publication number: WO2008150446A1
Application number: PCT/US2008/006854
Authority: WO
Inventors: Congxin Liang; Marcel Koenig; Yuanjun He
Original assignee: Congxin Liang; Marcel Koenig; Yuanjun He
Priority date: 2007-05-30
Filing date: 2008-05-30
Publication date: 2008-12-11
Also published as: TW200906825A; WO2008150446A8

Abstract

The invention provides inhibitors of protein kinases, such as an Src kinase, enzymes which has been implicated in processes such as cell migration, proliferation, and survival. The inhibitors include 2,5-disubstituted derivatives of thiazole wherein the substituents are as defined. The invention also provides a method of using the inhibitors in treatment of cancer, and a method of preparation of the inhibitors by a palladium-catalyzed coupling reaction.

Description

INHIBITORS OF PROTEIN KINASES

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority of U.S. Ser. No. 60/940,859, filed May 30, 2007, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION The field of the invention is molecular compositions that inhibit protein kinases such as Src protein kinase family members, and the use of these inhibitors in the treatment of disease such as cancer.

BACKGROUND Protein .kinases are enzymes that catalyze the phosphorylation of hydroxyl groups of tyrosine, serine, and threonine residues of proteins. Many aspects of cell life (for example, cell growth, differentiation, proliferation, cell cycle and survival) depend on protein kinase activities. Furthermore, abnormal protein kinase activity has been related to a host of disorders such as cancer and inflammation. Therefore, considerable effort has been directed to identifying ways to modulate protein kinase activities, hi particular, many attempts have been made to identify small molecules that act as protein kinase inhibitors.

Several aminothiazole derivatives have demonstrated activity as inhibitors of protein kinases (see for example: Lombardo, et al. J. Med. Chem. 2004, 47, 6658; Wityak et al. Bioorg. Med. Chem. Lett. 2003, 13, 4007). One of the compounds, dasatinib/BMS-354825, has shown special promise and it has been approved for Gleevec-resistant chronic myeloid leukemia (Shah et al. Science, 2004, 305, 401; Johnson et al. Clin. Cancer Res. 2005, 11, 6924). But this compound has also shown toxicity in a significant percent of patients (Dasatinib NDA filing, NDA 21-986, June 2, 2006). What is needed is a class of modified aminothiazole derivatives having both inhibitory activity and reduced toxicity.

Several patent applications have disclosed aminothiazoles as protein kinase inhibitors, for example, WO 2005077945, US006596746, US006979694, US2004054186, US20040054186, US20040073026, US20040077875, US20050261305, US20050288303, and US20060079563. However, compounds with high potency and selectivity for specific kinases, such as Src kinase, are still sought.

Thus, there is a remaining need for molecular entities that inhibit the action of Src kinase, which have potential for the treatment of cancer.

SUMMARY

The present invention is directed to substituted amino carboxamido thiazoles that are useful as protein kinase inhibitors. In particular, these thiazoles can function as inhibitors of kinases of the Src family, and are useful in the treatment of cancer.

An embodiment of the present invention concerns a compound of formula (I):

(I) wherein:

R¹ and R² are each independently at every occurrence H, (Ci-C₆)alkyl, (C₂- C₆)alkenyl or alkynyl, (C₃-C₈)cycloalkyl, or a 3-8 membered heterocyclyl, wherein any alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl groups is substituted with 0-3

Y;

X is NH or NR¹;

Ar¹ comprises an aryl or a heteroaryl group, which is substituted with 0-3 Y; Ar²-Z comprises an aryl or a heteroaryl group bearing a Z group, wherein the aryl or heteroaryl group is substituted with 0-2 additional Y groups;

Z comprises Y or an aryl or a heteroaryl group substituted with 0-3 Y groups; Y comprises halo, hydroxyl, cyano, thio, nitro, trifiuoromethyl, oxo, =N-OR', (d-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, OR¹, NH(R'), N(R')₂, SR', C(O)NH(R¹), C(O)N(R')₂, R¹C(O)N(R'), R¹C(O)O, R¹C(O), R¹SO₂, R'SO₂(Ci-C₃)alkyl, SO₂N(R')₂, N(R')SO₂R', ureyl bearing 0-3 R¹, (C₅-Ci₀)aryl, (C₅-Ci₀)heteroaryl, (C₅-

Cio)dihydroheteroaryl, (C₅-C i₀)tetrahydroheteroaryl, (C₃-Cio) mono- or bicyclic cycloalkyl, or (C₃-C_1O)HiOnO- or bicyclo-heterocyclyl, wherein each R¹ independently comprises hydrogen, aryl or (Ci-C₆)alkyl wherein any aryl or alkyl can be substituted with 0-3 Y groups, or where two R' groups taken together with a nitrogen atom to which they are attached form together with the nitrogen atom a heterocyclic ring comprising 0-2 additional heteroatoms, substituted with 0-3 Y groups; wherein when any Y is an alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, dihydroheteroaryl, tetrahydroheteroaryl, cycloalkyl or heterocyclyl group, Y may be further substituted by 0-3 Y; or a salt, tautomer, solvate, hydrate, or a prodrug thereof. Another embodiment according to the present invention concerns a method of preparation of the inventive compounds.

An embodiment of the present invention is directed a method of inhibiting a protein kinase, in vitro or in vivo, comprising combining a compound of the invention at an effective concentration with the protein kinase. The protein kinase can be inhibited in vitro, such as when carrying out an assay to determine the bioactivity of a specific compound of the invention. The protein kinase can also be inhibited in vivo, that is, within the body tissues of a living mammal. The protein kinase can be selected from the group consisting of the Src family of kinases, or can be AbI kinase. The protein kinase subject to inhibition by an inventive compound can be Src, Fyn, Lyn, Yes, or Lck, among others.

An embodiment of the present invention provides a method of treating a malcondition in a mammal that is mediated by abnormal protein kinase activities, such as abnormal Src kinase activity, comprising administration of a compound of the invention in a dosage, at a frequency, and for a duration to produce a beneficial effect on the mammal. The malcondition can be cancer and the mammal can be a human patient.

DETAILED DESCRIPTION OF THE INVENTION Definitions

"Treating" or "treatment" within the meaning herein refers to an alleviation of symptoms associated with a disorder or disease, or inhibition of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder. Similarly, as used herein, an "effective amount" or a "therapeutically effective amount" of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition.

In particular, a "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result by inhibition of Src protein kinase activity. A therapeutically effective amount is also one in which any toxic or detrimental effects of compounds of the invention are outweighed by the therapeutically beneficial effects. For example, in the context of treating cancer, a therapeutically effective amount of a Src inhibitor of the invention is an amount sufficient to control the cancer, mitigate the progress of the cancer, or relieve the symptoms of the cancer.

A "protein kinase" is an enzyme that catalyzes the phosphorylation of an amino acid residue of a protein. There are many enzymes of this type, with various specificities both in terms of the types of proteins of which they catalyze the phosphorylation and the nature of the amino acid residue that is phosphorylated. Kinase substrate specificities are highly varied and, typically, highly specific. Among the various amino acid residues of the target protein, tyrosine, serine, or threonine residues can be phosphorylated. Kinases are categorized into a plurality of families. The inventive compounds herein can inhibit, inter alia, the catalytic activity of members of the Src kinase family, including but not limited to Src, Fyn, Lyn, Yes, and Lck kinases. The inventive compounds can also inhibit AbI kinase.

All chiral, diastereomeric, racemic forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds used in the present invention can include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of the invention, as are mixtures of stereoisomers in various possible proportions, such as 75% enantiomerically enriched, 90% enantiomerically enriched, and so forth.

In general, "substituted" refers to an organic group as defined herein in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms such as, but not limited to, a halogen (i.e., F, Cl, Br, and I); an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxylamines, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups as well as other substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom such as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester, amide, imide, urethane, and urea groups; and nitrogen in imines, hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles.

The term "heteroatoms" as used herein refers to non-carbon and non-hydrogen atoms, and is not otherwise limited. Typical heteroatoms are N, O, and S. When sulfur (S) is referred to, it is understood that the sulfur can be in any of the oxidation states in which it is found, thus including sulfoxides (R-S(O)-R') and sulfones (R- S(O)₂-R'), unless the oxidation state is specified; thus, the term "sulfone" encompasses only the sulfone form of sulfur; the term "sulfide" encompasses only the sulfide (R-S-R') form of sulfur. When the phrases such as "heteroatoms selected from the group consisting of O, NH, NR¹ and S," or "[variable] is O, S . . ." are used, they are understood to encompass all of the sulfide, sulfoxide and sulfone oxidation states of sulfur.

Substituted ring groups such as substituted aryl, heterocyclyl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted aryl, heterocyclyl and heteroaryl groups may also be substituted with alkyl, alkenyl, and alkynyl groups as defined herein.

Alkyl groups include straight chain and branched alkyl groups and cycloalkyl groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n- butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. Representative substituted alkyl groups may be substituted one or more times with any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups may be mono- substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which may be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term "cycloalkenyl" alone or in combination denotes a cyclic alkenyl group.

The terms "carbocyclic" and "carbocycle" denote a ring structure wherein the atoms of the ring are carbon, hi some embodiments, the carbocycle has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms is 4, 5, 6, or 7. Unless specifically indicated to the contrary, the carbocyclic ring may be substituted with as many as N-I substituents wherein N is the size of the carbocyclic ring with for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, halogen groups and the like.

(Cycloalkyl)alkyl groups, also denoted cycloalkylalkyl, are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkyl group as defined above.

Alkenyl groups include straight and branched chain and cyclic alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to vinyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others. Cycloalkenyl groups include cycloalkyl groups having at least one double bond between 2 carbons. Thus for example, cycloalkenyl groups include but are not limited to cyclohexenyl, cyclopentenyl, cyclohexadienyl, cyclopentadienyl, and cyclohexadienyl groups.

(Cycloalkenyl)alkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above.

Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to - C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3) among others.

Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Thus aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain 6-14 carbons in the ring portions of the groups. Although the phrase "aryl groups" includes groups containing fused rings, such as fused aromatic- aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like), it does not include aryl groups that have other groups, such as alkyl or halogen groups, bonded to one of the ring members. Rather, groups such as tolyl are referred to as substituted aryl groups. Representative substituted aryl groups may be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with groups such as those listed above.

Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above. Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl group are alkenyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.

Heterocyclyl groups include aromatic and non-aromatic ring compounds containing 3 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, S, or P. In some embodiments, heterocyclyl groups include 3 to 20 ring members, whereas other such groups have 3 to 15 ring members. The phrase "heterocyclyl group" includes fused ring species including those including fused aromatic and non-aromatic groups. The phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. However, the phrase does not include heterocyclyl groups that have other groups, such as alkyl or halogen groups, bonded to one of the ring members. Rather, these are referred to as "substituted heterocyclyl groups". Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Representative substituted heterocyclyl groups may be mono- substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with groups such as those listed above.

Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Although the phrase "heteroaryl groups" includes fused ring compounds such as indolyl and 2,3-dihydro indolyl, the phrase does not include heteroaryl groups that have other groups bonded to one of the ring members, such as alkyl groups. Rather, heteroaryl groups with such substitution are referred to as "substituted heteroaryl groups". Representative substituted heteroaryl groups may be substituted one or more times with groups such as those listed above.

Additional examples of aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1- imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-l-yl, l,2,3-triazol-2-yl l,2,3-triazol-4-yl, l,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4- oxazolyl, 5-oxazolyl), thiazolyl (2 -thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2- pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5- pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4-pyridazinyl, 5- pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7- quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5- isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2- benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro- benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro- benzo[b]furanyl), benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7- benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro- benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro- benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro- benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1 -indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1 -benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6- benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4- benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzo thiazolyl), carbazolyl (1- carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,fjazepine (5H- dibenz[b,f]azepin-l-yl, 5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl, 5H- dibenz[b,fjazepine-4-yl, 5H-dibenz[b,f]azepine-5-yl), 10,1 l-dihydro-5H- dibenz[b,f]azepine (10,1 l-dihydro-5H-dibenz[b,f]azepine-l-yl, 10,1 l-dihydro-5H- dibenz[b,f]azepine-2-yl, 10, 11 -dihydro-5H-dibenz[b,f]azepine-3-yl, 10, 11 -dihydro- 5H-dibenz[b,f]azepine-4-yl, 10, 11 -dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.

Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heterocyclyl group as defined above. Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.

Heteroarylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above.

The term "alkoxy" refers to an oxygen atom connected to an alkyl group as defined above. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

The terms "aryloxy" and "arylalkoxy" refer to, respectively, an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy.

The term "amine" (or "amino") includes primary, secondary, and tertiary amines having, e.g., the formula -NR₂. Amines include but are not limited to -NH₂, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, aralkylamines, heterocyclylamines and the like.

The term "amide" (or "amido") includes C- and N-amide groups, i.e., -C(O)NR₂, and -NRC(O)R groups, respectively. Amide groups therefore include but are not limited to carbamoyl groups (-C(O)NH₂) and formamide groups (-NHC(O)H).

The term "urethane" (or "carbamyl") includes N- and O-urethane groups, i.e., -NRC(O)OR and -OC(O)NR₂ groups, respectively.

The term "urea" (or "ureyl") refers to groups of the formula N(R)C(O)N(R)₂. The term "sulfonamide" (or "sulfonamido") includes S- and N-sulfonamide groups, i.e., -SO₂NR₂ and -NRSO₂R groups, respectively. Sulfonamide groups therefore include but are not limited to sulfamoyl groups (-SO₂NH₂).

The term "amidine" or "amidino" includes groups of the formula -C(NR)NR₂. Typically, an amidino group is -C(NH)NH₂.

The term "guanidine" or "guanidino" includes groups of the formula -NRC(NR)NR₂. Typically, a guanidino group is -NHC(NH)NH₂.

The terms "comprising," "including," "composed of," are open-ended terms as used herein, and do not preclude the existence of additional elements or components. In a claim element, use of the forms "comprising," "having," or "including" means that whatever element is comprised, had, or included, is not necessarily the only element encompassed by the subject of the clause that contains that word.

In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. For example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, claims for X being bromine and claims for X being bromine and chlorine are fully described. Moreover, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any combination of individual members or subgroups of members of Markush groups. Thus, for example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, and Y is described as selected from the group consisting of methyl, ethyl, and propyl, claims for X being bromine and Y being methyl are fully described.

Compounds of the Invention

The present invention is directed to thiazole derivatives as described herein that are effective inhibitors of protein kinases. In particular, these thiazoles are inhibitors of a protein kinase of the Src family, including a protein kinase such as, but not limited to, Src, Fyn, Lyn, Yes, or Lck. The thiazoles can also inhibit the AbI kinase. As such the inventive compositions are useful for treatment of mal conditions wherein abnormal protein kinase activities are involved, such as cancer.

An embodiment of the present invention provides a compound of formula (I):

(I) wherein: R¹ and R² are each independently at every occurrence H, (Ci-C₆)alkyl, (C₂-

C₆)alkenyl or alkynyl, (C₃-C₈)cycloalkyl, or a 3-8 membered heterocyclyl, wherein any alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl groups is substituted with 0-3

Y;

X is NH or NR¹; Ar¹ comprises an aryl or a heteroaryl group, which is substituted with 0-3 Y;

Ai^-Z comprises an aryl or a heteroaryl group bearing a Z group, wherein the aryl or heteroaryl group is substituted with 0-2 additional Y groups;

Z comprises Y or an aryl or a heteroaryl group substituted with 0-3 Y groups; Y comprises halo, hydroxyl, cyano, thio, nitro, trifluoromethyl, oxo, =N-OR', (C,-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, OR¹, NH(R¹), N(R')₂, SR¹, C(O)NH(R¹), C(O)N(RO₂, R¹C(O)N(R¹), R¹C(O)O, R¹C(O), R¹SO₂, R'SO₂(C₁-C₃)alkyl, SO₂N(R')₂, N(R')SO₂R', ureyl bearing 0-3 R¹, (C₅-Ci₀)aryl, (C₅-C i₀)heteroaryl, (C₅- Cio)dihydroheteroaryl, (C₅-C ₁o)tetrahydroheteroaryl, (C₃-Cio) mono- or bicyclic cycloalkyl, or (C₃-Ci₀)mono- or bicyclo-heterocyclyl, wherein each R¹ independently comprises hydrogen, aryl or (CrC₆)alkyl wherein any aryl or alkyl can be substituted with 0-3 Y groups, or where two R¹ groups taken together with a nitrogen atom to which they are attached form together with the nitrogen atom a heterocyclic ring comprising 0-2 additional heteroatoms, substituted with 0-3 Y groups; wherein when any Y is an alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, dihydroheteroaryl, tetrahydroheteroaryl, cycloalkyl or heterocyclyl group, Y may be further substituted by 0-3 Y; or a salt, tautomer, solvate, hydrate, or a prodrug thereof. For example, R or R , or both, can be H. When R is H, the inventive compounds include 2,5-disubstituted thiazoles. When R² is H, the inventive compounds include 2-(arylamino) and 2-(heteroarylamino)thiazoles, wherein the aryl and heteroaryl groups can be substituted as defined herein. X can be NH, such that the inventive compounds include anilides or N- heteroarylcarboxamides bonded at the 5-position of the thiazole ring. Alternatively, X can be NR', wherein R¹ is as defined herein. A specific example is X = N-CH₃.

Ar¹ can be aryl or heteroaryl, wherein the aryl or heteroaryl can be substituted with 0-3 Y groups. For example, Ar¹ can be phenyl, such as substituted phenyl, such that the inventive compound comprises an anilide of a thiazole-5-carboxylate. The phenyl group can be substituted with Y groups as defined herein; specifically Y can comprise halo or alkyl, such that the Ar¹ phenyl group can be substituted with a halo group and an alkyl group, such as a chloro group and a methyl group. For example, the inventive compound can be a 2-chloro-6-methylanilide of a thiazole-5- carboxylate.

Ar² can be an aryl or a heteroaryl group. For example, Ar² can be a phenyl, pyridinyl, or pyrimidinyl group, wherein the phenyl or the heteroaryl group is substituted with 0-3 Y groups as are defined herein. For example, Ar² can be a pyrimidyl group substituted with Y. Y can be alkyl, such as methyl. A specific example of Ar² is a 2-methyl-pyrimid-4-yl group. Other specific examples are a 2- pyridyl group or a phenyl group.

Ar² can be further substituted; for example, Ar² can comprise a 2-methyl- pyrimid-4-yl bearing another Y group at the 6-position. For example, Ar² can comprise

R³

X¹^X²

R⁴ wherein a wavy line signifies a point of attachment (i.e., to the thiazole 2-amino group); R³ and R⁴ each independently H, (Ci-C₆)alkyl, (C₃-C₈)mono- or bicyclic cycloalkyl, (C₃-C₈)mono-or bicyclic heterocyclyl, aryl, or heteroaryl; wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-3 Y; and wherein X and X are independently at each occurrence N or CR¹. Thus, when X and X² are both N, and R³ is methyl, this structure exemplifies the subset of inventive compounds wherein Ar² is a 2-methylpyrimid-4-yl group bearing a 6-substituent termed R⁴ that falls within the class of groups defined as Y herein. It is recognized that the definition of the compound of formula (I) is iterative, i.e., the Y group is defined, for example, that when Y is aryl or heteroaryl, Y can bear another Y group independently selected from the list of options, such that substitution can be reiteratively repeated. It is also recognized that other factors are present, such as bioactivity, bioavailability, solubility, and chemical synthetic accessibility, that will be determinative of the maximum size of a molecule of the invention. Specific examples of inventive compounds are provided in Table 1 and in the

Examples section herein.

Methods of Preparation

An embodiment of the present invention is directed to a method of preparing inventive compounds. More specifically, the inventors herein provide a method of preparing a compound of formula (I), comprising contacting a compound of formula (II):

(H), wherein L is a leaving group, and a boronate compound of formula (III):

Z-B(OR⁵)₂

(HI), wherein Z comprises an aryl or a heteroaryl group substituted with 0-3 Y groups; wherein R⁵ is H, an alkyl group, a boronate protecting group, or wherein two R⁵ groups taken together form a diester of the boronate compound; in the presence of a palladium complex, for sufficient time and at a sufficient temperature to provide a product of formula (I):

(I) wherein Z comprises an aryl or a heteroaryl group substituted with 0-3 Y groups. More specifically, Z can be a halo group, such as a chloro group, that is coupled with the boronate of formula (III) in a Suzuki reaction to provide the inventive compounds. The palladium compound bringing about the coupling reaction can be, for example, PdCl₂(PPh₃)₂, or Pd(PPh₃)₄.

Compositions and Combination Treatments

Another aspect of an embodiment of the invention provides compositions of the compounds of the invention, alone or in combination with another Src inhibitor or another type of kinase inhibitor or another type of therapeutic agent, or all of the above. As set forth herein, compounds of the invention include stereoisomers, tautomers, solvates, prodrugs, salts such as pharmaceutically acceptable salts, and mixtures thereof. Compositions containing a compound of the invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practice of Pharmacy, 19th Ed., 1995. The compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.

Typical compositions include a compound of the invention which inhibits the enzymatic activity of Src kinase, and a pharmaceutically acceptable excipient which may be a carrier or a diluent. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of an ampoule, capsule, sachet, paper, or other container. When the active compound is mixed with a carrier, or when the carrier serves as a diluent, it may be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid carrier, for example contained in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The formulations can be mixed with auxiliary agents which do not deleteriously react with the active compounds. Such additives can include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and/or coloring substances preserving agents, sweetening agents or flavoring agents. The compositions can also be sterilized if desired.

The route of administration may be any route which effectively transports the active compound of the invention which inhibits the enzymatic activity of the Src kinase to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred.

If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils may be employed as solvents or suspending agents. Preferably, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides. For injection, the formulation may also be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these. The compounds may be formulated for parenteral administration by injection such as by bolus injection or continuous infusion. A unit dosage form for injection may be in ampoules or in multi-dose containers.

The formulations of the invention may be designed to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art. Thus, the formulations may also be formulated for controlled release or for slow release.

Compositions contemplated by the present invention may include, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the formulations may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents. Such implants may employ known inert materials such as silicones and biodegradable polymers, e.g., polylactide-polyglycolide. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).

For nasal administration, the preparation may contain a compound of the invention which inhibits the enzymatic activity of the Src kinase, dissolved or suspended in a liquid carrier, preferably an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizing agents, e.g., propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabens.

For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed. A typical tablet that may be prepared by conventional tabletting techniques may contain:

Core:

Active compound (as free compound or salt thereof) 250 mg Colloidal silicon dioxide (Aerosil)® 1.5 mg Cellulose, microcryst. (Avicel)® 70 mg

Modified cellulose gum (Ac-Di-Sol)® 7.5 mg Magnesium stearate Ad. Coating:

HPMC approx. 9 mg *Mywacett 9-40 T approx. 0.9 mg

*Acylated monoglyceride used as plasticizer for film coating.

A typical capsule for oral administration contains compounds of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule. A typical injectable preparation is produced by aseptically placing 250 mg of compounds of the invention into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of sterile physiological saline, to produce an injectable preparation. The compounds of the invention may be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of a malcondition that is mediated through the action of Src, for example, cancer. Such mammals include also animals, both domestic animals, e.g. household pets, farm animals, and non-domestic animals such as wildlife.

The compounds of the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from about 0.05 to about 5000 mg, preferably from about 1 to about 2000 mg, and more preferably between about 2 and about 2000 mg per day may be used. A typical dosage is about 10 mg to about 1000 mg per day. In choosing a regimen for patients it may frequently be necessary to begin with a higher dosage and when the condition is under control to reduce the dosage. The exact dosage will depend upon the activity of the compound, mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge. Src inhibitor activity of the compounds of the invention may be determined by use of an in vitro assay system which measures the inhibition of Src. Inhibition constants (i.e., Kj or IC₅₀ values as known in the art) for the kinase inhibitors of the invention may be determined by the method described in the Examples.

Generally, the compounds of the invention are dispensed in unit dosage form including from about 0.05 mg to about 1000 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.

Usually, dosage forms suitable for oral, nasal, pulmonal or transdermal administration include from about 125 μg to about 1250 mg, preferably from about 250 μg to about 500 mg, and more preferably from about 2.5 mg to about 250 mg, of the compounds admixed with a pharmaceutically acceptable carrier or diluent.

An embodiment of the invention also encompasses prodrugs of a compound of the invention which on administration undergo chemical conversion by metabolic or other physiological processes before becoming active pharmacological substances. Conversion by metabolic or other physiological processes includes without limitation enzymatic (e.g, specific enzymatically catalyzed) and non-enzymatic (e.g., general or specific acid or base induced) chemical transformation of the prodrug into the active pharmacological substance. In general, such prodrugs will be functional derivatives of a compound of the invention which are readily convertible in vivo into a compound of the invention. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

In another embodiment, there are provided methods of making a composition of a compound described herein including formulating a compound of the invention with a pharmaceutically acceptable carrier or diluent. In some embodiments, the pharmaceutically acceptable carrier or diluent is suitable for oral administration. In some such embodiments, the methods may further include the step of formulating the composition into a tablet or capsule. In other embodiments, the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, the methods further include the step of lyophilizing the composition to form a lyophilized preparation.

The compounds of the invention may be used in combination with i) one or more other Src inhibitors and/or ii) one or more other types of protein kinase inhibitors and/or one or more other types of therapeutic agents which may be administered orally in the same dosage form, in a separate oral dosage form (e.g., sequentially or non-sequentially) or by injection together or separately (e.g., sequentially or non-sequentially).

Accordingly, in another aspect the invention provides combinations, comprising: a) a compound of the invention as described herein; and b) one or more compounds comprising: i) other compounds of the present invention, ii) other protein kinase inhibitors, such as inhibitors of PYK2 or FAK, or iii) other anti-cancer agents.

Combinations of the invention include mixtures of compounds from (a) and (b) in a single formulation and compounds from (a) and (b) as separate formulations. Some combinations of the invention may be packaged as separate formulations in a kit. In some embodiments, two or more compounds from (b) are formulated together while a compound of the invention is formulated separately.

The dosages and formulations for the other agents to be employed, where applicable, will be as set out in the latest edition of the Physicians' Desk Reference.

Methods of Treatment An embodiment of the present invention provides a method for inhibiting a protein kinase, such as Src, with a compound of the invention. The method involves contacting the protein kinase with a suitable concentration of an inventive compound. The contacting can take place in vitro, for example in carrying out an assay to determine the kinase inhibitory activity of an inventive compound undergoing experimentation related to a submission for regulatory approval. For example, an assay can include a control compound, an experimental inventive compound, the kinase enzyme under study such as Src, a suitable substrate for the enzyme, and optionally a reporter group of some kind such as a fluorescent or a radiolabeled reporter group, along with suitable solutions and buffers for carrying out the assay. The components of the assay can be provided as a kit, including the components as listed above plus informational material, such as a brochure or a computer-readable disc.

The method for inhibiting a protein kinase, such as Src, can also be carried out in vivo, that is, within the living body of a mammal, such as a human patient or a test animal. The inventive compound can be supplied to the living organism via one of the routes as described above, e.g., orally, or can be provided locally within the body tissues, for example by injection of a tumor within the organism. In the presence of the inventive compound, inhibition of the kinase takes place, and the effect thereof can be studied.

An embodiment of the present invention provides a method of treatment of a malcondition in a patient that is mediated by abnormal protein kinase activities, wherein the patient is administered the inventive compound in a dosage, at a frequency, and for a duration to produce a beneficial effect on the patient. The inventive compound can be administered by any suitable means, examples of which are described above. As discussed above, it is believed that cancer may be one such malcondition that is mediated by abnormal protein kinase activities, specifically by abnormal Src activities, such as in malignant cells undergoing metastasis. It is believed that inhibition of such abnormal activities may serve to either kill metastasizing cells, inactivate them, reduce their mobility within the body, or reverse their metastatic transformation.

It is believed that there are at least two mechanisms by which inhibition of Src may act to effectively treat cancer. In the first mechanism, certain tumors are believed to be activated or driven by Src, such that inhibition of Src will serve to kill the tumor cells. In the second mechanism, Src is believed to be involved in the adhesion of metastasizing cancer cells in circulation in the lymph system to sites wherein they bring about metastatic transformation of new cell populations. In these cases, blocking adhesion serves not only to prevent the induction of new sites of the cancer, but the circulating metastasized cells are caused to undergo apoptosis, resulting in their death.

EXAMPLES

Table 1

Exemplary Compounds of the Invention

Abbreviations

ACN acetonitrile røc-BINAP rac-2,2 ' -Bis(diphenylphosphino)- 1,1 ' -binaphthyl

DCM dichloromethane

DMSO dimethylsulfoxide

EtOAc ethyl acetate

HPLC high pressure liquid chromatography

LC-ESIMS liquid chromatography-electrospray ionization mass spectrometry

M molar

MeOH methanol

Pd₂(dba)₃ Tris(dibenzylideneacetone)dipalladium(0).

TFA trifluoracetic acid

Synthetic Examples

General Procedures:

Method A: Sodium hydride (60% in mineral oil, 4-6 eq.) was suspended in THF. 2- (6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)-iV-(4- methoxybenzyl)thiazole-5-carboxamide (1 eq.) was added. It was stirred for 10' at room temperature. The alcohol (4-6 eq.) was added and it was heated in a Biotage Initiator microwave synthesizer at 160 ⁰C for 1 h. It was diluted with ethyl acetate, washed with brine and dried over sodium sulfate. The solvent was removed and the residue was purified by silica gel chromatography or prep. HPLC.

Method B: The product from Method A was dissolved in 50% TFA/DCM (ca. 2 mL/0.1 mmol substrate) and triflic acid (ca. 0.2 mL/0.1 mmol substrate). It was stirred for 4 h at room temperature. It was diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. The solvent was removed and the residue was purified by silica gel chromatography or prep. HPLC. Example 1

2-(6-chloro-2-methylpyrimidin-4-ylamino)-iV-(2-chloro-6-methylphenyl)thiazole-

5-carboxamide

The synthesis of 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6- methylphenyl)thiazole-5-carboxamide, a common starting material of the present examples, is described in full detail in Lombardo, LJ. ; et al. J. Med. Chem. (2004), 47, 6658-6661, supporting information. The p-methoxybenzyl (PMB) substituted carboxyamido group derivative can be prepared by treatment of the carboxamide with p-methoxybenzylchloride and base.

For the preparations of 2-chlorothiazole and 4-Amino-6-chloro-2- methylpyrimidine, building blocks used therein, the following procedures were substituted: 2-Chlorothiazole

// \\ _^ // \\ s' S ^Cl

(Carla Boga, et al. J. Organometallic. Chemistry (1999), 588, 155-159)

To a solution of thiazole (5.0g, 58.7mmol) in anhydrous THF (60 mL) at -78 ⁰C, n-BuLi (1.6 M in hexane, 44 mL, 70.4 mmol) was added dropwise over 20min, after stirring at -78 ⁰C for 15min, 2,2,2-trichloroacetyl chloride (6.6 mL, 58.7 mmol) in anhydrous THF (40 mL) was added dropwise into the orange mixture. The reaction mixture was stirred for an additional 30min at -78 ⁰C then the reaction was quenched with sat'd NH₄Cl solution (100 mL). After extraction with Et₂O (2x15OmL), the combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated at reduced pressure. The crude was purified by silica gel chromatography (0-20% Et₂O/pentane) to obtain the desired compound (4.95g, isolated yield; 71%). 1H NMR (400 MHz, CDCl₃) δ 7.50 (d, J= 4.0 Hz, IH), 7.15 (d, J- 4.0 Hz, IH). 4-Amino-6-chloro-2-methylpyrimidine

4,6-Dichloro-2-methylpyrimidine (10.45 g, 64.11 mmol) was dissolved in 7 M ammonia in MeOH (115 mL) in a pressure flask. The reaction mixture was heated at 1 10 ⁰C for 24 h, then was evaporated to dryness and the residue re-crystallized from a small volume of water (40 ml, then refrigerated at 5 ⁰C). The crystals were washed with ice cold water to give the title compound as a colorless solid (6.56 g, 71%). 1H-NMR (400 MHz, d₆-DMSO) δ 7.10 (br s, 2H), 6.26 (s, IH), 2.28 (s, 3H).

Example 2: iV-(2-chloro-6-methylphenyl)-2-(6-(2-(diethylainino)ethoxy)-2-methylpyriinidin- 4-ylamino)thiazole-5-carboxamide

Methods A and B were applied. The TFA salt of the title compound was obtained as a solid.

¹H-NMR (400 MHz, d₆-DMSO) δ 11.95 (s, IH), 9.98 (s, IH), 9.53 (broad s, IH), 8.28 (s, IH), 7.46-7.39 (m, IH), 7.31-7.24 (m, 2H), 6.30 (s, IH), 4.62 (t, J = 5.0 Hz, 2H), 3.52 (m, 2H), 3.22 (m, 4H), 2.55 (s, 3H), 2.24 (s, 3H), 1.22 (t, J - 7.4 Hz, 6H); MS (m/z): 475.15 [M+l]⁺.

Example 3;

7V-(2-chloro-6-methylphenyl)-2-(2-methyl-6-(2-(2-oxopyrrolidin-l- yl)ethoxy)pyrimidin-4-ylamino)thiazole-5-carboxamide

Methods A and B were applied. The title compound was obtained as a pale yellow solid. ¹H-NMR (400 MHz, d₆-DMSO) δ 11.85 (s, IH), 9.95 (s, IH), 8.26 (s, IH), 7.41-7.39 (m, IH), 7.30-7.26 (m, 2H), 6.19 (s, IH), 4.41 (t, J = 5.2 Hz, 2H), 3.42 (m, 4H), 2.53 (s, 3H), 2.24 (s, 3H), 2.19 (m, 2H), 1.90 (m, 2H); MS (m/z): 487.1 [M+l]⁺.

Example 4:

(R)-7V-(2-chloro-6-methylphenyl)-2-(2-methyl-6-((5-oxopyrrolidin-2- yl)methoxy)pyrimidin-4-ylamino)thiazole-5-carboxamide

Methods A and B were applied. The title compound was obtained as a solid.

¹H-NMR (400 MHz, d₆-DMSO) δ 11.88 (s, IH), 9.95 (s, IH), 8.26 (s, IH), 7.87 (s, IH), 7.42-7.39 (m, IH), 7.29-7. ,26 (m, 2H), 6.24 (s, IH), 4.24 (m, 2H), 3.88 (m, IH), 2.50 (s, 3H), 2.24 (s, 3H), 2.14 (m, 3H), 1.85 (m, IH); MS (m/z): 473.1 [M+l]⁺.

Example 5:

N-(2-chloro-6-methylphenyl)-2-(2-methyl-6-((tetrahydro-2H-pyran-4- yl)methoxy)pyrimidin-4-ylamino)thiazole-5-carboxamide

Methods A and B were applied. The title compound was obtained as a white solid.

¹H-NMR (400 MHz, d₆-DMSO) δ 11.81 (s, IH), 9.94 (s, IH), 8.26 (s, IH), 7.41-7.39 (m, IH), 7.29-7.26 (m, 2H), 6.21 (s, IH), 4.14 (d, J= 6.4 Hz, 2H), 3.87 (m, 2H), 3.35- 3.29 (m, 5H), 2.24 (s, 3H), 1.99 (m, IH), 1.65-1.62 (m, 2H), 1.33-1.29 (m, 2H); MS (m/z): 474.2 [M+l]⁺. Example 6: iV-(2-chloro-6-methylphenyl)-2-(2-methyl-6-(2-morpholinoethoxy)pyriinidin-4- ylamino)thiazole-5-carboxamide

¹H-NMR (400 MHz, d₆-DMSO) δ 11.95 (broad s, IH), 10.32 (broad s, IH), 9.98 (s, IH), 8.28 (s, IH), 7.41-7.39 (m, IH), 7.29-7.24 (m, 2H), 6.31 (s, IH), 4.66 (t, J= 4.6 Hz, 2H), 3.97 (m, 2H), 3.72 (m, 2H), 3.59-3.51 (m, 4H), 3.17 (m, 2H), 2.55 (s, 3H), 2.24 (s, 3H); MS (m/z): 489.15 [M+l]⁺.

Example 7: iV-(2-chloro-6-methylphenyl)-2-(2-methyl-6-(2-(2-oxooxazolidin-3- yl)ethoxy)pyrimidin-4-ylamino)thiazole-5-carboxamide

Methods A and B were applied. The title compound was obtained as a pale yellow solid.

¹H-NMR (400 MHz, d₆-DMSO) δ 11.85 (broad s, IH), 9.95 (s, IH), 8.26 (s, IH), 7.42-7.39 (m, IH), 7.29-7.24 (m, 2H), 6.20 (s, IH), 4.45 (t, J= 5.2 Hz, 2H), 4.24 (t, J = 8.0 Hz, 2H), 3.62 (t, J= 8.0 Hz, 2H), 3.53 (t, J= 5.2 Hz, 2H), 2.53 (s, 3H), 2.24 (s, 3H); MS (m/z): 489.0 [M+l]⁺. Example 8:

_J/V-(2-chloro-6-methylphenyl)-2-(2-methyl-6-(piperidin-4-yloxy)pyrimidin-4- ylamino)thiazole-5-carboxamide

Methods A and B were applied. The TFA salt of the title compound was obtained as a white solid.

¹H-NMR (400 MHz, d₆-DMSO) δ 11.89 (br s, IH), 9.96 (s, IH), 8.50 (br s, IH), 8.44 (br s, IH), 8.27 (s, IH), 7.41 (dd, J= 1.4, 7.4 Hz, IH), 7.31-7.24 (m, 2H), 6.23 (s, IH), 5.33-5.29 (m, IH), 3.29-3.22 (m, 2H), 3.18-3.10 (m, 2H), 2.53 (s, 3H), 2.24 (s, 3H), 2.15-2.09 (m, 2H), 1.90-1.82 (m, 2H); MS (m/z): 458.9 [M+l]⁺.

Example 9:

7V-(2-chloro-6-methylphenyl)-2-(2-methyl-6-(l-methylpiperidin-4- yloxy)pyrimidin-4-ylamino)thiazole-5-carboxamide

Methods A and B were applied. The TFA salt of the title compound was obtained as a white solid. 1H-NMR (400 MHz, d₆-DMSO) δ 11.94, 11.86 (2s, IH), 9.95 (s, 2H), 9.43, 9.33 (2br s, IH), 8.27 (2s, IH), 7.41 (dd, J= 1.8, 7.4 Hz, 2H), 7.31-7.24 (m, 2H), 6.27, 6.21 (2s, IH), 5.37 (br s, 0.5H), 5.26-5.21 (m, 0.5H), 3.52-3.48 (m, IH), 3.38-3.32 (m, IH), 3.21-3.13 (m, 2H), 2.84 (d, J = 4.8 Hz₅ 1.5 H), 2.80 (d, J = 4.8 Hz, 1.5H), 2.53 (2s, 3H), 2.31-2.24 (m, IH), 2.24 (s, 3H), 2.16-2.09 (m, IH), 2.05-1.98 (m, IH), 1.82-1.73 (m, IH); MS (m/z): 473.3 [M+l]⁺. Example 10:

2-(6-(l-acetylpiperidin-4-yloxy)-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6- methylphenyl)thiazole-5-carboxamide

N-(2-chloro-6-methylphenyl)-N-(4-methoxybenzyl)-2-(2-methyl-6-(piperidin- 4-yloxy)pyrimidin-4-ylamino)thiazole-5-carboxamide (28 mg, 0.048 mmol) was dissolved in acetic anhydride (1.0 mL) and pyridine (3.0 mL). It was stirred for 5 h at room temperature. The solvent was removed and the residue was purified by silica gel chromatography (DCM/MeOH gradient). The resulting white solid was dissolved in 10% TFA/DCM (2.0 mL) and triflic acid (0.2 mL). It was stirred for 14 h at room temperature. It was diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. The solvent was removed and the residue was purified by prep. HPLC. The title compound was obtained as a white solid.

¹H-NMR (400 MHz, d₆-DMSO) δ 11.82 (br s, IH), 9.94 (s, IH), 8.26 (s, IH), 7.41 (dd, J= 1.8, 7.4 Hz, IH), 7.31-7.24 (m, 2H), 6.21 (s, IH), 5.30-5.26 (m, IH), 3.86- 3.80 (m, IH), 3.69-3.64 (m, IH), 3.39-3.33 (m, IH), 3.29-3.22 (m, IH), 2.53 (s, 3H), 2.24 (s, 3H), 2.02 (s, 3H), 2.02-1.96 (m, IH), 1.93-1.88 (m, IH), 1.69-1.62 (m, IH), 1.57-1.50 (m, IH); MS (m/z): 501.1 [M+l]⁺.

Example 11: iV-(2-chloro-6-methylphenyl)-2-(2-methyl-6-(l-propionylpiperidin-4- yloxy)pyrimidin-4-ylamino)thiazole-5-carboxamide

iV-(2-chloro-6-methylphenyl)-2-(2-methyl-6-(piperidin-4-yloxy)pyrimidin-4- ylamino)thiazole-5-carboxamide (27 mg, 0.059 mmol), propionic acid (9 μL, 0.12 mmol), HOBt (16 mg, 0.12 mmol), EDCI (22 mg, 0.11 mmol) and triethylamine (8 μL, 0.057 mmol) were dissolved in DMF (3 mL). It was stirred for 14 h at room temperature. It was diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. The solvent was removed and the residue was purified by prep. HPLC. The title compound was obtained as a white solid. 1H-NMR (400 MHz, d₆-DMSO) δ 11.82 (br s, IH), 9.94 (s, IH), 8.26 (s, IH), 7.41 (dd, J= 1.6, 7.6 Hz, IH), 7.31-7.24 (m, 2H), 6.20 (s, IH), 5.30-5.25 (m, IH), 3.88- 3.83 (m, IH), 3.71-3.66 (m, IH), 3.74-3.32 (m, IH), 3.29-3.23 (m, IH), 3.52 (s, 3H), 3.34 (q, J= 7.3 Hz, 2H), 2.24 (s, 3H), 2.00-1.89 (m, 2H), 1.66-1.60 (m, IH), 1.60- 1.49 (m, IH), 0.99 (t, J= 7.4 Hz, 3H); MS (m/z): 515.0 [M+l]⁺.

Example 12: Λ^-(2-chloro-6-methylphenyl)-2-(2-methyl-6-(l-methylpyrrolidin-3- yloxy)pyrimidin-4-ylamino)thiazole-5-carboxamide

¹H-NMR (400 MHz, d₆-DMSO) δ 11.90 (br s, IH), 10.09 (vbr s, IH), 9.97 (s, IH), 8.27 (s, IH), 7.41 (dd, J= 1.8, 7.4 Hz, IH), 7.31-7.25 (m, 2H), 6.28 (s, IH), 5.66 (br s, 0.65H), 5.57 (br s, 0.35H), 3.78-3.70 (m, IH), 3.45-3.40 (m, IH), 3.28-3.23 (m,

IH), 3.17-3.12 (m, IH), 2.92 (br d, 1.05H), 2.86 (br d, 1.95H), 2.55 (s, 3H), 2.32-2.26 (m, IH), 2.40 (s, 3H), 2.13-2.08 (m, IH); MS (m/z): 459.1 [M+l]⁺.

Example 13: 7V-(2-chloro-6-methylphenyl)-2-(2-methyl-6-(quinuclidin-3-yloxy)pyrimidin-4- ylamino)thiazole-5-carboxamide

¹H-NMR (400 MHz, d₆-DMSO) δ 11.93 (s, IH), 9.97 (s, IH), 9.60 (br s, IH), 8.27 (s, IH), 7.41 (dd, J = 1.8, 7.4 Hz, IH), 7.31-7.25 (m, 2H), 6.28 (s, IH), 5.32-5.26 (m, IH), 3.81-3.75 (m, 2H), 3.31-3.20 (m, 5H), 2.54 (s, 3H), 2.41-2.38 (m, IH), 2.40 (s, 3H), 2.12-2.07 (m, IH), 1.97-1.88 (m, IH), 1.82-1.77 (m, IH); MS (m/z): 485.2 [M+l]⁺.

Example 14: N-(2-chloro-6-methylphenyl)-2-(2-methyl-4,5'-bipyrimidin-6-ylamino)thiazole-5- carboxamide

To 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6- methylphenyl)thiazole-5-carboxamide (250 mg, 0.634 mmol) in dioxane (10 mL) was added pyrimidin-5-ylboronic acid (94 mg, 0.759 mmol), PdCl₂(PPh₃)₂ (89 mg, 0.127 mmol) and Na₂CO₃ (2 M, 1 mL, 1.902 mmol). The mixture was stirred under Argon overnight in an oil bath (12O⁰C). The reaction mixture was cooled to room temperature and water was added, extracted with 10% MeOH in CHCl₃ (3x50 mL). The organic layers were washed with brine and dried over anhydrous Na₂SO₄. The solvent was removed and the crude was purified with preparative HPLC (ACN/ 0.1 % TFA in water) to obtain the title compound as a yellow solid (180 mg, 52%). 1H-NMR (400 MHz, d₆-DMSO) δ 12.31 (br s, IH), 10.02 (s, IH), 9.36 (s, 2H), 9.35 (s, IH), 8.34 (s, IH), 7.43 (s, IH), 7.41 (d, J= 1.6 Hz, IH), 7.32-7.25 (m, 2H), 2.71 (s, 3H), 2.26 (s, 3H); MS (m/z): 438.2 [M+l]⁺. Example 15:

Λ^f-(2-chloro-6-methylphenyl)-2-(6-(4-methoxypyridin-3-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide

28

A mixture of 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6- methylphenyl)thiazole-5-carboxamide (39 mg, 0.079 mmol), 4-methoxy-3- pyridineboronic acid (15 mg, 0.22 mmol), Pd(PPh₃)₄ (13 mg, 0.011 mmol), sodium carbonate (35 mg, 0.33 mmol) in THF (3.5 mL) and water (0.35 mL) was microwave heated at 160 ⁰C for 1 h. The solvent was removed and the crude was purified by preparative HPLC (ACΝ/ 0.1 % TFA in water) and lyophilized to yield the title compound as a slightly yellow fluffy solid. 1H-NMR (400 MHz, d₆-DMSO) δ 12.11 (br s, IH), 9.99 (s, IH), 8.84 (d, J = 2.4 Hz, IH), 8.32 (s, IH), 8.29 (d, J = 2.4 Hz, IH), 7.41 (dd, J = 1.6, 7.6 Hz, IH), 7.36-7.18 (m, 3H), 7.00 (d, J = 8.4 Hz, IH), 3.94 (s, 3H), 2.67 (s, 3H), 2.25 (s, 3H); MS (m/z): 466.2 [M+l]⁺.

Example 16: 7V-(2-chloro-6-methylphenyl)-2-(2-methyl-6-phenylpyrimidin-4-ylamino)thiazole- 5-carboxamide

29

A mixture of 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6- methylphenyl)-N-(4-methoxybenzyl)thiazole-5-carboxamide (50 mg, 0.097 mmol), phenylboronic acid (13 mg, 0.11 mmol), Pd(PPh₃)₄ (31 mg, 0.027 mmol), sodium carbonate (30 mg, 0.28 mmol) in THF (3.0 mL) and water (0.30 mL) was microwave heated at 160 ⁰C for 1 h. The solvent was removed and the residue was purified by silica gel chromatography. The product was dissolved in 50% TFA in DCM (3 mL) and triflic acid (0.2 mL). The reaction mixture was stirred for 3 h at it, diluted with EtOAc, washed with sat. sodium bicarbonate, brine, dried over sodium sulfate and the solvent was removed. The residue was purified by preparative HPLC (ACN/ 0.1 % TFA in water) and lyophilized to yield the title compound as a slightly yellow fluffy solid.

¹H-NMR (400 MHz, d₆-DMSO) δ 12.14 (br s, IH), 9.99 (s, IH), 8.32 (s, IH), 8.05- 8.02 (m, 2H), 7.59-7.54 (m, 3H), 7.42 (dd, J = 1.6, 7.6 Hz, IH), 7.35 (s, IH), 7.32- 7.25 (m, 2H), 2.69 (s, 3H), 2.26 (s, 3H); MS (m/z): 466.2 [M+l]⁺.

Example 17:

7V-(2-chloro-6-methylphenyl)-2-(2'-methoxy-2-methyl-4,5'-bipyrimidin-6- ylamino)thiazole-5-carboxamide

32 A mixture of 2-(6-chloro-2-methylpyrimidin-4-ylamino)-7V-(2-chloro-6- methylphenyl)-N-(4-methoxybenzyl)thiazole-5-carboxamide (37 mg, 0.072 mmol), 2- methoxypyrimidin-5-boronic acid (15 mg, 0.097 mmol), Pd(PPh₃)₄ (24 mg, 0.021 mmol), sodium carbonate (24 mg, 0.23 mmol) in THF (3.0 mL) and water (0.30 mL) was microwave heated at 160 ⁰C for 1 h. The solvent was removed and the residue was purified by silica gel chromatography. The product was dissolved in 50% TFA in DCM (3 mL) and triflic acid (0.2 mL). The reaction mixture was stirred for 3 h at rt, diluted with EtOAc, washed with sat. sodium bicarbonate, brine, dried over sodium sulfate and the solvent was removed. The residue was purified by preparative HPLC (ACN/ 0.1 % TFA in water) and lyophilized to yield the title compound as a fluffy solid.

¹H-NMR (400 MHz, d₆-DMSO) δ 12.21 (br s, IH), 10.00 (s, IH), 9.18 (s, 2H), 8.32 (s, IH), 7.41 (dd, J = 1.6, 7.6 Hz, IH), 7.33-7.27 (m, 3H), 4.02 (s, 3H), 2.68 (s, 3H), 2.25 (s, 3H); MS (m/z): 468.2 [M+l]⁺. Example 18:

N-(2-chloro-6-methylphenyl)-2-(2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-

3-yl)pyrimidin-4-ylamino)thiazole-5-carboxamide

1>^Suzuki ,

2) TF/VTfOH

34

A mixture of 2-(6-chloro-2-methylpyrimidin-4-ylamino)-iV-(2-chloro-6- methylphenyl)-N-(4-methoxybenzyl)thiazole-5-carboxamide (38 mg, 0.074 mmol), morpholino(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanone (34 mg, 0.11 mmol), Pd(PPh₃)₄ (28 mg, 0.024 mmol), sodium carbonate (23 mg, 0.22 mmol) in THF (3.0 mL) and water (0.30 mL) was microwave heated at 160 ⁰C for 1 h. The solvent was removed and the residue was purified by silica gel chromatography. The product was dissolved in 50% TFA in DCM (3 mL) and triflic acid (0.2 mL). It was stirred for 3 h at rt, diluted with EtOAc, washed with sat. sodium bicarbonate, brine, dried over sodium sulfate and the solvent was removed. The residue was purified by preparative HPLC (ACΝ/ 0.1 % TFA in water) and lyophilized to yield the title compound as a slightly yellow fluffy solid.

¹H-NMR (400 MHz, d₆-DMSO) δ 12.24 (br s, IH), 10.01 (s, IH), 9.24 (d, J = 2.0 Hz, IH), 8.78 (d, J= 2.0 Hz, IH), 8.40 (t, J= 2.0 Hz, IH), 8.34 (s, IH), 7.42 (s, IH), 7.41 (d, J = 14.0 Hz, IH), 7.32-7.25 (m, 2H), 3.67 (br s, partially covered by water, 8H), 2.70 (s, 3H), 2.26 (s, 3H); MS (m/z): 550.2 [M+l]⁺.

Example 19: iY-(2-chloro-6-methylphenyl)-2-(2-methyl-2'-(4-methylpiperazin-l-yl)-4,5'- bipyrimidin-6-ylamino)thiazole-5-carboxamide

4

A mixture of 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6- methylphenyl)-N-(4-methoxybenzyl)thiazole-5-carboxamide (46 mg, 0.089 mmol), 2-

(4-methylpiperazin-l-yl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine

(35 mg, 0.12 mmol), Pd(PPh₃)₄ (30 mg, 0.026 mmol), sodium carbonate (26 mg, 0.25 mmol) in THF (3.0 mL) and water (0.30 mL) was microwave heated at 160 ⁰C for 1 h.

The solvent was removed and the residue was purified by silica gel chromatography.

The product was dissolved in 50% TFA in DCM (3 mL) and triflic acid (0.2 mL).

The reaction mixture was stirred for 3 h at rt, diluted with EtOAc, washed with sat. sodium bicarbonate, brine, dried over sodium sulfate and the solvent was removed. The residue was purified by preparative HPLC (ACΝ/ 0.1 % TFA in water) and lyophilized to yield the TFA salt of the title compound as a slightly yellow fluffy solid.

¹H-NMR (400 MHz, d₆-DMSO) δ 12.12 (br s, IH), 9.99 (s, IH), 9.83 (br s, IH), 9.04

(s, 2H), 8.32 (s, IH), 7.41 (dd, J = 1.6 Hz, 7.6 Hz, IH), 7.32-7.26 (m, 3H), 4.83 (d, J = 14.0 Hz, 2H), 3.56-3.35 (m, 4H), 3.12 (t, 2H), 2.86 (s, 3H), 2.65 (s, 3H), 2.25 (s,

3H); MS (m/z): 536.2 [M+l]⁺.

Example 20:

N-(2-chloro-6-methylphenyl)-2-(6-(6-cyanopyridin-3-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide

5

A mixture of 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6- methylphenyl)-N-(4-methoxybenzyl)thiazole-5-carboxamide (41 mg, 0.080 mmol), 5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)picolinonitrile (27 mg, 0.12 mmol), Pd(PPh₃)₄ (28 mg, 0.024 mmol), sodium carbonate (27 mg, 0.25 mmol) in THF (3.0 mL) and water (0.30 mL) was microwave heated at 160 ⁰C for 1 h. The solvent was removed and the residue was purified by silica gel chromatography. The product was dissolved in 50% TFA in DCM (3 mL) and triflic acid (0.2 mL). The reaction mixture was stirred for 3 h at rt, diluted with EtOAc, washed with sat. sodium bicarbonate, brine, dried over sodium sulfate and the solvent was removed. The residue was purified by preparative HPLC (ACN/ 0.1 % TFA in water) and lyophilized to yield the title compound as a slightly yellow fluffy solid. 1H-NMR (400 MHz, d₆-DMSO) δ 12.32 (br s, IH), 10.02 (s, IH), 9.33 (d, J= 1.6 Hz, IH), 8.60 (dd, J= 2.2, 8.2 Hz, IH), 8.34 (s, IH), 8.23 (dd, J- 0.6, 8.2 Hz, IH), 7.45 (s, IH), 7.42 (dd, J =1.6, 7.6 Hz, IH), 7.32-7.25 (m, 2H), 2.71 (s, 3H), 2.26 (s, 3H); MS (m/z): 462.2 [M+l]⁺.

Example 21:

N-(2-chloro-6-methylphenyl)-2-(6-(6-hydroxypyridin-3-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide

D Suzuki 2) TFAHTOH

8

A mixture of 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6- methylphenyl)-N-(4-methoxybenzyl)thiazole-5-carboxamide (33 mg, 0.064 mmol), 5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-ol (19 mg, 0.086 mmol), Pd(PPh₃)₄ (10 mg, 0.009 mmol), sodium carbonate (22 mg, 0.21 mmol) in THF (3.0 mL) and water (0.30 mL) was microwave heated at 160 ⁰C for 1 h. The solvent was removed and the residue was purified by silica gel chromatography. The product was dissolved in 50% TFA in DCM (3 mL) and triflic acid (0.2 mL). The reaction mixture was stirred for 3 h at rt, diluted with EtOAc, washed with sat. sodium bicarbonate, brine, dried over sodium sulfate and the solvent was removed. The residue was purified by preparative HPLC (ACN/ 0.1 % TFA in water) and lyophilized to yield the title compound as a slightly yellow solid. 1H-NMR (400 MHz, d₆-DMSO) δ 12.04 (br s, IH), 9.97 (s, IH), 8.30 (s, IH), 8.17 (br s, IH), 8.00 (dd, J - 2.6 Hz, IH), 7.41 (dd, J = 1.6, 7.2 Hz, IH), 7.31-7.23 (m, 2H), 7.09 (s, IH), 6.54 (br s , 2H), 6.49 (d, J = 9.6 Hz, IH), 2.62 (s, 3H), 2.25 (s, 3H); MS (m/z): 453.2 [M+l]⁺.

Example 22: 7V-(2-chloro-6-methylphenyl)-2-(2-methyl-6-(lH-pyrazol-4-yl)pyrimidin-4- ylamino)thiazole-5-carboxamide

A mixture of 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6- methylphenyl)-N-(4-methoxybenzyl)thiazole-5-carboxamide (33 mg, 0.064 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole-l-carboxylate (25 mg, 0.085 mmol), Pd(PPh₃)₄ (24 mg, 0.021 mmol), sodium carbonate (22 mg, 0.21 mmol) in TΗF (3.0 mL) and water (0.30 mL) was microwave heated at 160 ⁰C for 1 h. The solvent was removed and the residue was purified by silica gel chromatography. The product was dissolved in 50% TFA in DCM (3 mL) and triflic acid (0.2 mL). The reaction mixture was stirred for 3 h at rt, diluted with EtOAc, washed with sat. sodium bicarbonate, brine, dried over sodium sulfate and the solvent was removed. The residue was purified by preparative HP LC (ACN/ 0.1 % TFA in water) and lyophilized to yield the title compound as a slightly yellow fluffy solid. 1 H-NMR (400 MHz, d₆-DMSO) δ 12.21 (br s, IH), 10.00 (s, IH), 8.32 (s, IH), 8.26 (s, 2H), 7.41 (dd, J - 1.6, 7.6 Hz, IH), 7.31-7.25 (m, 2H), 7.09 (s, IH), 2.64 (s, 3H), 2.25 (s, 3H); MS (m/z): 426.2 [M+l]⁺.

Example 23: iV-(2-chloro-6-methylphenyl)-2-(2-methyl-6-(lH-pyrazol-5-yl)pyrimidin-4- ylamino)thiazole-5-carboxamide

A mixture of 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6- methylphenyl)-N-(4-methoxybenzyl)thiazole-5-carboxamide (38 mg, 0.074 mmol), l//-ρyrazol-5-ylboronic acid (11 mg, 0.098 mmol), Pd(PPh₃)₄ (30 mg, 0.026 mmol), sodium carbonate (26 mg, 0.25 mmol) in THF (3.0 mL) and water (0.30 mL) was microwave heated at 160 ⁰C for 1 h. The solvent was removed and the residue was purified by silica gel chromatography. The product was dissolved in 50% TFA in DCM (3 mL) and triflic acid (0.2 mL). The reaction mixture was stirred for 3 h at rt, diluted with EtOAc, washed with sat. sodium bicarbonate, brine, dried over sodium sulfate and the solvent was removed. The residue was purified by preparative HPLC (ACN/ 0.1 % TFA in water) and lyophilized to yield the title compound as a slightly yellow fluffy solid.

¹H-NMR (400 MHz, d₆-DMSO) δ 12.22 (br s, IH), 10.00 (s, IH), 8.32 (s, IH), 7.88 (d, J = 2.0 Hz, IH), 7.46 (s, IH), 7.41 (dd, J = 1.6, 7.6 Hz, IH), 7.31-7.25 (m, 2H), 6.91 (d, J= 2.0 Hz, IH), 2.67 (s, 3H), 2.25 (s, 3H); MS (m/z): 426.2 [M+l]⁺.

Example 24: iV-(2-chloro-6-methylphenyl)-2-(2-methyl-6-(pyridm-3-yl)pyrimidin-4- ylamino)thiazole-5-carboxamide

To 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6- methylphenyl)thiazole-5-carboxamide (30mg, 0.076mmol) THF (2.OmL) was added pyridin-3-ylboronic acid (11.2 mg, 0.091mmol), Pd(PPh₃)₄ (21.2 mg, 0.018 mmol) and Na₂CO₃ (2 M, 0.15 mL, 0.3mmol). The mixture was stirred under Argon for 5 min, and then the mixture was heated at 160 ⁰C in microwave reactor for Ih. The reaction was cooled to room temperature and water was added, extracted with 10% MeOH in CHCl₃ (3*20 mL). The organic layers was combined and concentrated under reduced pressure. The crude was purified with prep-HPLC to obtain the title compound as a yellow solid. LC-ESIMS observed [M+H]⁺ 437.2 ; ¹H NMR (400 MHz, DMSO-d₆) δ 12.25 (broad s, IH), 10.01 (s, IH), 9.24 (s, IH), 8.78 (d, J= 5.2 Hz, IH), 8.48 (d, J= 8.0 Hz, IH), 8.33 (s, IH), 7.70-7.67 (m, IH), 7.42-7.41 (m, 2H), 7.32-7.25 (m, 2H), 2.71 (s, 3H), 2.26 (s, 3H).

Example 25: iV-(2-chloro-6-methylphenyI)-2-(2-methyl-6-(pyridin-4-yl)pyrimidin-4- ylamino)thiazole-5-carboxamide

A similar procedure to that of the synthesis ofN-(2-chloro-6-methylphenyl)-2- (2-methyl-6-(pyridin-3-yl)pyrimidin-4-ylamino)thiazole-5-carboxamide was followed.

N-(2-chloro-6-methylphenyl)-2-(2-methyl-6-(pyridin-4-yl)pyrimidin-4- ylamino)thiazole-5-carboxamide: LC-ESIMS observed [M+H]⁺ 437.3; ¹H NMR (400 MHz, DMSOd₆) δ 12.30 (br s, IH), 10.02 (s, IH), 8.82 (d, J= 5.2 Hz, 2H), 8.34 (s, IH), 8.03 (d, J= 5.6 Hz, 2H), 7.46 (s, IH), 7.43-7.41 (m, IH), 7.30-7.21 (m, 2H), 2.71 (s, 3H), 2.26 (s, 3H).

Example 26:

N-(2-chloro-6-methylphenyl)-2-(2-methyl-6-(pyridin-2-yl)pyrimidin-4- ylamino)thiazole-5-carboxamide

N-(2-chloro-6-methylphenyl)-iV-(4-methoxybenzyl)-2-(2-inethyl-6-(pyridin-2- yl)pyrimidin-4-ylamino)thiazole-5-carboxamide

To 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)- N-(4-methoxybenzyl)thiazole-5-carboxamide (50 mg, 0.097 mmol) in THF (2.0 mL) was added pyridin-2-ylboronic acid (14.3 mg, 0.1 lόmmol), Pd(PPh₃ )₄ (112.3mg, 0.029mmol) and Na₂CO₃ (2 M, 0.15 mL, 0.3 mmol). The mixture was stirred under Argon for 5 min, and then the mixture was heated at 160 ⁰C in a microwave reactor for Ih. The reaction mixture was cooled to room temperature and water was added, extracted with 10% MeOH in CHCl₃ (3x20 mL). The organic layers were combined and concentrated under reduced pressure. The crude was purified in silica gel to obtain the title compound. LC-ESIMS observed [M+H]⁺ 556.8. 7V-(2-chloro-6-methylphenyl)-2-(2-methyl-6-(pyridin-2-yl)pyrimidin-4- ylamino)thiazole-5-carboxamide

N-(2-chloro-6-methylphenyl)-N-(4-methoxybenzyl)-2-(2-memyl-6-(pyridin-2- yl)pyrimidin-4-ylamino)thiazole-5-carboxamide was dissolved in TFA/DCM (1 :1, 2 mL), and excess triflic acid (0.05 mL) was added to the solution. The reaction mixture was stirred at room temperature until completion (by LC/MS). The reaction mixture was diluted with CH₂Cl₂ (20 mL) and then neutralized with sat'd NaHCO₃. The organic layer was separated and the aqueous layer was extracted with 10% MeOH in CHCl₃ (3x20 mL). The organic layers were combined and concentrated under reduced pressure. The crude was purified with prep-HPLC to obtain the title compound as a yellow solid. LC-ESIMS observed [M+H]⁺ 437.24; ¹H NMR (400 MHz, DMSO-d₆) δ 10.03 (s, IH), 8.78 (d, J= 4.0 Hz, IH), 8.41 (d, J= 8.0 Hz, IH), 8.35 (s, IH), 8.06 (td, J= 7.8 Hz, 1.6 Hz, IH), 7.87 (s, IH), 7.63-7.60 (m, IH), 7.43-7.41 (m, IH), 7.32-7.25 (m, 2H), 2.74 (s, 3H), 2.26(s, 3H)

Example 27: iV-(2-chloro-6-methylphenyl)-2-(6-(6-methoxypyridin-3-yl)-2-methylpyriinidin-4- ylamino)thiazole-5-carboxamide

7V-(2-chloro-6-methylphenyl)-Λ^L(4-methoxybenzyl)-2-(6-(6-methoxypyridin-3-yl)- 2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide

The procedure is similar to that of synthesis of N-(2-chloro-6-methylphenyl)- N-(4-methoxybenzyl)-2-(2-methyl-6-(pyridin-2-yl)pyrimidin-4-ylamino)thiazole-5- carboxamide.

N-(2-chloro-6-methylphenyl)-N-(4-methoxybenzyl)-2-(6-(6-methoxypyridin-3-yl)-2- ) methylpyrimidin-4-ylamino)thiazole-5-carboxamide: LC-ESIMS observed [M+H]⁺ 587.19.

iV-(2-chloro-6-methylphenyl)-2-(6-(6-methoxypyridin-3-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide

A similar procedure to that of the synthesis of 7V-(2-chloro-6-methylphenyl)-2-

(2-methyl-6-(pyridin-2-yl)pyrimidin-4-ylamino)thiazole-5-carboxamide was used. N-(2-chloro-6-methylphenyl)-2-(6-(6-methoxypyridin-3-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide: LC-ESIMS observed [M+H]⁺ 467.2; ¹H ΝMR (400 MHz, DMSO-d₆) δ 12.12 (br s, IH), 9.99 (s, IH), 8.84 (d, J= 2.4 Hz, IH), 8.32 (s, IH), 8.32-8.29 (m, IH), 7.42-7.41 (m, IH), 7.30-7.25 (m, 3H), 7.00 (d, J= 8.8Hz, IH), 3.95 (s, 3H), 2.67 (s, 3H), 2.25 (s, 3H).

Example 28: 7V-(2-chloro-6-methylphenyl)-2-(2-methyl-6-(6-(4-methylpiperazin-l-yl)pyridin- 3-yl)pyrimidin-4-ylamino)thiazole-5-carboxamide

2

7V-(2-chloro-6-methylphenyl)-Λ^-(4-methoxybenzyl)-2-(2-methyl-6-(6-(4- methylpiperazin-l-yl)pyridin-3-yl)pyrimidin-4-yIamino)thiazole-5-carboxamide

N-(2-chloro-6-methylphenyl)-N-(4-methoxybenzyl)-2-(2-methyl-6-(6-(4- methylpiperazin-l-yl)pyridin-3-yl)pyrimidin-4-ylamino)thiazole-5-carboxamide: LC- ESIMS observed [M+H]⁺ 655.2.

iV-(2-chloro-6-ιnethylphenyl)-2-(2-methyl-6-(6-(4-methylpiperazin-l-yl)pyridin- 3-yl)pyrimidin-4-ylamino)thiazole-5-carboxamide

A similar procedure to that of the synthesis of N-(2-chloro-6-methylphenyl)-2- (2-methyl-6-(pyridin-2-yl)pyrimidin-4-ylamino)thiazole-5-carboxamide was followed.

N-(2-chloro-6-methylphenyl)-2-(2-methyl-6-(6-(4-methylpiperazin-l-yl)pyridin-3- yl)pyrimidin-4-ylamino)thiazole-5-carboxamide: LC-ESIMS observed [M+H]⁺ 535.14.

Example 29:

7V-(2-chloro-6-methylphenyl)-2-(2-methyl-6-(2-morpholinopyridin-4- yl)pyrimidin-4-ylamino)thiazole-5-carboxamide

N-(2-chloro-6-methylphenyl)-N-(4-methoxybenzyl)-2-(2-methyl-6-(2- morpholinopyridin-4-yl)pyrimidin-4-ylamino)thiazole-5-carboxamide

The procedure is similar to that of the synthesis of N-(2-chloro-6- methylphenyl)-N-(4-methoxybenzyl)-2-(2-methyl-6-(pyridin-2-yl)pyrimidin-4- ylamino)thiazole-5-carboxamide was followed. N-(2-chloro-6-methylphenyl)-N-(4-methoxybenzyl)-2-(2-methyl-6-(2- morpholinopyridin-4-yl)pyrimidin-4-ylamino)thiazole-5-carboxamide: LC-ESIMS observed [M+H]⁺ 642.22.

7V-(2-chloro-6-methylphenyl)-2-(2-methyl-6-(2-moφholinopyridin-4-yl)pyrimidin-4- ylamino)thiazole-5-carboxamide:

LC-ESIMS observed [M+H]⁺ 522.2; ¹H NMR (400 MHz, DMSOd₆) δ 12.05 (br s, IH), 9.98 (s, IH), 8.80 (d, J= 2.4 Hz, IH), 8.31 (s, IH), 8.17 (dd, J= 8.8, 2.4 Hz, IH), 7.42-7.40 (m, IH), 7.31-7.25 (m, 2H), 7.23 (s, IH), 7.00 (d, J= 8.8 Hz, IH), 3.73-3.70 (m, 4H), 3.61-3.58 (m, 4H), 2.64 (s, 3H), 2.25 (s, 3H). Example 30:

7V-(2-chloro-6-methylphenyl)-2-(6-(3,5-dimethylisoxazol-4-yl)-2- methylpyrimidin-4-ylamino)thiazole-5-carboxamide

iV-(2-chloro-6-methylphenyl)-2-(6-(3,5-dimethylisoxazol-4-yl)-2- methylpyrimidin-4-ylamino)-iV-(4-methoxybenzyl)thiazole-5-carboxainide

A similar procedure to that of the synthesis of 7V-(2-chloro-6-methylphenyl)-jV-(4- methoxybenzyl)-2-(2-methyl-6-(pyridin-2-yl)pyrimidin-4-ylamino)thiazole-5- carboxamide was followed.

N-(2-chloro-6-methylphenyl)-2-(6-(3,5-dimethylisoxazol-4-yl)-2-methylpyrimidin-4- ylamino)-N-(4-methoxybenzyl)thiazole-5-carboxamide: LC-ESIMS observed [M+H]⁺ 575.2.

A similar procedure to that of the synthesis of N-(2-chloro-6-methylphenyl)-2-

(2-methyl-6-(pyridin-2-yl)pyrimidin-4-ylamino)thiazole-5-carboxamide was followed. N-(2-chloro-6-methylphenyl)-2-(6-(3,5-dimethylisoxazol-4-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide: LC-ESIMS observed [M+H]⁺ 455.2; ¹H NMR (400 MHz, DMSOd₆) δ 12.12 (br s, IH), 10.01 (s, IH), 8.32 (s, IH), 7.41 (d, J= 6.4 Hz, IH), 7.31-7.25 (m, 2H), 7.10 (s, IH), 2.65 (2 s, 6H), 2.43 (s, 3H), 2.25 (s, 3H).

Example 31:

7V-(2-chloro-6-methylphenyl)-2-(3-(pyrimidin-5-yl)phenylamino)thiazole-5- carboxamide

2-(3-bromophenylamino)-A'-(2-chloro-6-methylphenyl)-iV-(4- methoxybenzyl)thiazole-5-carboxamide

3-bromoaniline (127 mg, 0.735 mmol) was added to a suspension of NaH (60% dispersion, 88.4 mg, 2.205 mmol) in THF (3 mL) at 0 ⁰C. The mixture was stirred at room temperature for 30 min and then treated with 2-chloro-iV-(2-chloro-6- methylphenyl)-7V-(4-methoxybenzyl)thiazole-5-carboxamide (200 mg, 0.49 mmol). The resulting mixture was heated at reflux for 4 h, cooled to rt and diluted with H₂O (0.5 mL). The mixture was acidified with 1 N HCl and extracted with DCM. The combined extracts were dried and concentrated under reduced pressure to give the crude which was purified by flash chromatography. LC-ESIMS observed [M+H]⁺ 542.10. N-(2-chloro-6-methylphenyl)-A'-(4-methoxybenzyl)-2-(3-(pyrimidin-5- yl)phenylamino)thiazole-5-carboxamide

A similar procedure to that of the synthesis of N-(2-chloro-6-methylphenyl)- N-(4-methoxybenzyl)-2-(2-methyl-6-(pyridin-2-yl)pyrimidin-4-ylamino)thiazole-5- carboxamide was followed.

N-(2-chloro-6-methylphenyl)-N-(4-methoxybenzyl)-2-(3-(pyrimidin-5- yl)phenylamino)thiazole-5-carboxamide. LC-ESIMS observed [M+H]⁺ 542.2.

Λ'-(2-chloro-6-methylphenyl)-2-(3-(pyrimidin-5-yl)phenylainino)thiazole-5- carboxamide

N-(2-chloro-6-methylphenyl)-2-(3-(pyrimidin-5-yl)phenylamino)thiazole-5- carboxamide: LC-ESIMS observed [M+H]⁺ 422.2; ¹H ΝMR (400 MHz, DMSOd₆) δ 10.84 (br s, IH), 9.95 (s, IH), 9.23 (s, IH), 9.11 (s, 2H), 8.16 (s, IH), 8.01 (s, IH), 7.76 (d, J= 7.2 Hz, IH), 7.53 (t, J= 7.8 Hz, IH), 7.45-7.39 (m, 2H), 7.30-7.24 (m, 2H), 2.23 (s, 3H). Example 32:

N-(2-chloro-6-methylphenyl)-2-(3-(pyridin-3-yl)phenylamino)thiazole-5- carboxamide

N-(2-chloro-6-methylphenyl)-Λ'-(4-methoxybenzyl)-2-(3-(pyridin-3- yl)phenylamino)thiazole-5-carboxamide

The procedure is similar to that of the synthesis of 7V-(2-chloro-6- methylphenyl)-N-(4-methoxybenzyl)-2-(2-methyl-6-(pyridin-2-yl)pyrimidin-4- ylamino)thiazole-5-carboxamide.

N-(2-chloro-6-methylphenyl)-N-(4-methoxybenzyl)-2-(3-(pyridin-3- yl)phenylamino)thiazole-5-carboxamide: LC-ESIMS observed [M+H]⁺ 541.08.

Λ^r-(2-chloro-6-methylphenyl)-2-(3-(pyridin-3-yl)phenylamino)thiazole-5- carboxamide

N-(2-chloro-6-methylphenyl)-2-(3-(pyridin-3-yl)phenylamino)thiazole-5-carboxamide as a TFA salt. LC-ESIMS observed [M+H]⁺421.1; ¹H ΝMR (400 MHz, DMSOd₆) δ 10.86 (br s, IH), 9.95 (s, IH), 9.06 (br s, IH), 8.79 (br s, IH), 8.42 (d, J= 8.0 Hz, IH), 8.16 (s, IH), 8.04 (s, IH), 7.85-7.82 (m, IH), 7.73 (d, J= 7.6Hz, IH), 7.53 (t, J = 8.0 Hz, IH), 7.44-7.39 (m, 2H), 7.30-7.24 (m, 2H), 2.24 (s, 3H).

Example 33: iV-(2-chloro-6-methylphenyl)-2-(4-(pyriinidin-5-yl)pyridin-2-ylamino)thiazole-5- carboxamide

2-Amino-iV-(2-chloro-6-methylphenyl)-Λ^L(4-methoxybenzyl)thiazole-5- carboxamide

To 2-chloro-N-(2-chloro-6-methylphenyl)-N-(4-methoxybenzyl)thiazole-5- carboxamide (125 mg, 0.3 mmol) was added a ammonia solution in methanol (7 N, 5 mL) in a microwave vial. The vial was sealed and heated in a microwave reactor for 2 h at 145°C. Completion of the reaction was detected by LC/MS. The solvent was removed to obtain the desired 2-amino-N-(2-chloro-6-methylphenyl)-7V-(4- methoxybenzyl)thiazole-5-carboxamide. LC-ESIMS observed [M+H]⁺ 388.1

5-(2-chloropyridin-4-yl)pyrimidine

The procedure is similar to that of synthesis of N-(2-chloro-6-methylphenyl)-

7V-(4-methoxybenzyl)-2-(2-methyl-6-(pyridin-2-yl)pyrimidin-4-ylamino)thiazole-5- carboxamide.

5-(2-chloropyridin-4-yl)pyrimidine (isolated yield 42%). LC-ESIMS observed [M+H]⁺ 192.2 7V-(2-chloro-6-methylphenyl)-iV-(4-methoxybenzyl)-2-(4-(pyriinidin-5-yl)pyridin- 2-ylamino)thiazole-5-carboxamide

To the microwave vial were added 5-(2-chloropyridin-4-yl)pyrimidine (27.8 mg, 0.145 mmol), 2-amino-N-(2-chloro-6-methylphenyl)-N-(4- methoxybenzyl)thiazole-5-carboxamide (67mg, 0.174 mmol), Pd₂(dba)₃ (13.3mg, 0.0145 mmol), røc-BIΝAP (81 mg, 0.029 mmol), t-BuOΝa (20 mg, 0.218 mmol) and toluene (3.0 mL) under Argon. The vial was sealed and heated in a microwave reactor for 15 min at 130 ⁰C. The cooled mixture was filtered through Celite. The filtrate was concentrated and the crude was purified by silica gel chromatography to obtain the desired product which was dried under reduced pressure for the following step. LC-ESIMS observed [M+H]⁺ 543.1.

Λ^r-(2-chloro-6-methylphenyl)-2-(4-(pyrimidin-5-yl)pyridin-2-ylamino)thiazole-5- carboxamide

7V-(2-chloro-6-methylphenyl)-2-(4-(pyrimidin-5-yl)pyridin-2-ylamino)thiazole-5- carboxamide.

LC-ESIMS observed [M+H]⁺ 423.2; ¹H ΝMR (400 MHz, DMSOd₆) δ 11.90 (br s, IH), 9.91 (s, IH), 9.31 (s, IH), 9.18 (s, IH), 8.53 (d, J= 5.2 Hz, IH), 8.28 (s, IH), 7.46 (dd, J= 5.2, 1.2 Hz, IH), 7.42-7.39 (m, 2H), 7.29-7.26 (m, 2H), 2.25 (s, 3H). Example 34:

N-(2-chloro-6-methylphenyl)-2-(2-methyl-6-(6-methylpyridin-3-yl)pyrimidin-4- ylamino)thiazole-5-carboxamide

N-(2-chloro-6-methylphenyl)-iV-(4-methoxybenzyl)-2-(2-methyl-6-(6- methylpyridin-3-yl)pyrimidin-4-ylamino)thiazole-5-carboxamide

The procedure is similar to that of the synthesis of N-(2-chloro-6- methylphenyl)-iV-(4-methoxybenzyl)-2-(2-methyl-6-(pyridin-2-yl)pyrimidin-4- yl amino)thiazole- 5 -carboxamide.

7V-(2-chloro-6-methylphenyl)-N-(4-methoxybenzyl)-2-(2-methyl-6-(6-methylpyridin- 3-yl)pyrimidin-4-ylamino)thiazole-5-carboxamide. LC-ESIMS observed [M+H]⁺ 571.1.

N-(2-chloro-6-methylphenyl)-2-(2-methyl-6-(6-methylpyridin-3-yl)pyrimidin-4- ylamino)thiazole-5-carboxamide, TFA salt: LC-ESIMS observed [M+H]⁺451.2; ¹H NMR (400 MHz, DMSO-d₆) δ 12.25 (br s, IH), 10.01 (s, IH), 9.16 (d, J= 1.6 Hz, IH), 8.52 (dd, J= 8.0, 1.6 Hz, IH), 8.34 (s, IH), 7.66 (d, J= 8.4 Hz, IH), 7.43-7.40 (m, 2H), 7.32-7.25 (m, 2H), 2.70 (s, 3H), 2.65 (s, 3H), 2.25 (s, 3H).

Example 35:

7V-(2-chloro-6-methylphenyl)-2-(5-methylisoxazol-3-ylainino)thiazole-5- carboxamide

38

A mixture of 2-chloro-N-(2-chloro-6-methylphenyl)-N-(4- methoxybenzyl)thiazole-5-carboxamide (49 mg, 0.12 mmol), 3-amino-5- methylisoxazole (14.5 mg, 0.15 mmol), Pd₂(dba)₃ (11 mg, 0.012 mmol), rac-BINAP (15 mg, 0.024 mmol), sodium tert-butoxide (18 mg, 0.18 mmol) in toluene (2.5 mL) was heated in a Biotage Initiator microwave synthesizer at 130 ⁰C for 15'. The reaction was quenched with sat. sodium carbonate, it was extracted with EtOAc, washed with brine, dried over sodium sulfate and the solvent was removed. The crude was purified by preparative HPLC. The product was dissolved in 50% TFA in DCM (3 mL) and triflic acid (0.2 mL). The reaction mixture was stirred for 3 h at it, diluted with EtOAc, washed with sat. sodium bicarbonate, brine, dried over sodium sulfate and the solvent was removed. The residue was purified by preparative HPLC (ACN/ 0.1 % TFA in water) to yield the title compound as a white solid. 1H-NMR (400 MHz, d₆-DMSO) δ 11.56 (br s, IH), 9.95 (s, IH), 8.19 (s, IH), 7.40 (dd, J= 1.8, 7.4 Hz, IH), 7.30-7.24 (m, 2H), 6.13 (dd, J= 0.56 Hz, IH), 2.38 (s, 3H), 2.23 (s, 3H); MS (m/z): 349.2 [M+l]⁺. Example 36:

7V-(2-chloro-6-methylphenyl)-2-(3-methylisoxazol-5-ylamino)thiazole-5- carboxamide

39

A mixture of 2-chloro-JV-(2-chloro-6-methylphenyl)-iV-(4- methoxybenzyl)thiazole-5-carboxamide (49 mg, 0.12 mmol), 5-amino-3- methylisoxazole (14.5 mg, 0.15 mmol), Pd₂(dba)₃ (11 mg, 0.012 mmol), rac-BINAP (15 mg, 0.024 mmol), sodium tert-butoxide (18 mg, 0.18 mmol) in toluene (2.5 mL) was heated in a Biotage Initiator microwave synthesizer at 130 ⁰C for 15'. The reaction was quenched with sat. sodium carbonate, it was extracted with EtOAc, washed with brine, dried over sodium sulfate and the solvent was removed. The crude was purified by preparative HPLC. The product was dissolved in 50% TFA in DCM (3 mL) and triflic acid (0.2 mL). The reaction mixture was stirred for 3 h at rt, diluted with EtOAc, washed with sat. sodium bicarbonate, brine, dried over sodium sulfate and the solvent was removed. The residue was purified by preparative HPLC (ACN/ 0.1 % TFA in water) to yield the title compound as a white solid. 1H-NMR (400 MHz, d₆-DMSO) δ 12.26 (br s, IH), 10.03 (s, IH), 8.18 (s, IH), 7.40 (dd, J= 1.9, 7.4 Hz, IH), 7.30-7.24 (m, 2H), 6.02 (br s, IH), 2.23 (s, 3H), 2.19 (s, 3H); MS (m/z): 349.1 [M+l]⁺.

Example 37: iV-(2-chloro-6-methylphenyl)-2-(l-methyl-lH-pyrazol-3-ylamino)thiazole-5- carboxamide

40 A mixture of 2-chloro-N-(2-chloro-6-methylphenyl)-N-(4- methoxybenzyl)thiazole-5-carboxamide (70 mg, 0.17 mmol), l-methyl-lH-pyrazol-3- amine (20 mg, 0.20 mmol), Pd₂(dba)₃ (16 mg, 0.017 mmol), røc-BINAP (21 mg, 0.034 mmol), sodium tert-butoxide (25 mg, 0.26 mmol) in toluene (3.0 mL) was heated in a Biotage Initiator microwave synthesizer at 130 ⁰C for 15'. The reaction was quenched with sat. sodium carbonate, it was extracted with EtOAc, washed with brine, dried over sodium sulfate and the solvent was removed. The crude was purified by silica gel chromatography. The product was dissolved in 50% TFA in DCM (3 mL) and triflic acid (0.2 mL). The reaction mixture was stirred for 3 h at rt, diluted with EtOAc, washed with sat. sodium bicarbonate, brine, dried over sodium sulfate and the solvent was removed. The residue was purified by preparative ΗPLC (ACN/ 0.1 % TFA in water) to yield the title compound as a white solid. 1H-NMR (400 MHz, d₆-DMSO) δ 11.08 (br s, IH), 9.80 (s, IH), 8.12 (s, IH), 7.62 (d, J= 2.2 Hz, IH), 7.39 (dd, J= 1.7, 7.5 Hz, IH), 7.29-7.22 (m, 2H), 5.94 (d, J= 2.2 Hz, IH), 3.79 (s, 3H), 2.22 (s, 3H); MS (m/z): 347.1 [M+l]⁺.

Example 38: Src Biochemical Assay

The compounds were assayed for biochemical activity by Upstate Ltd at Dundee, United Kingdom, according to the following procedure. In a final reaction volume of 25 μl, cSrc (h) (5-10 mU) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μM KVEKIGEGTYGVVYK (Cdc2 peptide), 10 mM MgAcetate and [γ- ³³P-ATP] (specific activity approx. 500 cpm/pmol, concentration as required). The reaction is initiated by the addition of the MgATP mix. After incubation for 40 minutes at room temperature, the reaction is stopped by the addition of 5 μl of a 3% phosphoric acid solution. 10 μl of the reaction is then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting.

Example 39: Cellular Assay: Src phosphorylation NIH3T3 cells over-expressing chicken Src are plated at a density of 20,000 cells/ well (96 well plate) in DMEM +10% FBS. Following cell attachment for 4 hours the chemical test compounds are added to a final concentration of 0.1% DMSO (Compounds are diluted in DMSO to lOOμM. Subsequent serial dilutions are made 1 :4 from 25μM to 24nM in DMSO). Following 1 hour incubation at 37°C media is removed and cells are lysed with 120ul/well lysis buffer (Cell Signaling #9803 +0.2% protease inhibitor, Sigma P 1860 +ImM Na3VO4) overnight at 4°C. P-Src is quantitated by ELISA (Invitrogen P-Src [pY418} ELISA cat#KHO0171) using lOOul oflysate. Most compounds showed IC50 of <10O nM in this assay. Compound 30 and dasatinib showed IC50 <10 nM.

Example 40: Cytotoxicity

Human cell lines are maintained in the appropriate media at 37°C and 5% CO2. Cells are plated at a density 5000-10,000 cells/well (96 well plate) in complete growth media. Following cell attachment (1-12 hours) the medium is replaced by fresh medium and the chemical test compounds are added to a final concentration of 1 % DMSO. Following a 48 hour incubation at 37°C cell viability is measured by resazurin reduction.

Claims

CLAIMSWhat is claimed is:

1. A compound of formula (I):

(I) wherein:

Y;

X is NH or NR¹;

Ar¹ comprises an aryl or a heteroaryl group, which is substituted with 0-3 Y;

Ar² -Z comprises an aryl or a heteroaryl group bearing a Z group, wherein the aryl or heteroaryl group is substituted with 0-2 additional Y groups;

Z comprises Y or an aryl or a heteroaryl group substituted with 0-3 Y groups;

Y comprises halo, hydroxyl, cyano, thio, nitro, trifiuoromethyl, oxo, =N-OR', (C,-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, OR¹, NH(R'), N(R')₂, SR¹, C(O)NH(R'), C(O)N(R')₂, R¹C(O)N(R'), R¹C(O)O, R¹C(O), R¹SO₂, R¹SO₂(C, -C₃)alkyl, SO₂N(R')₂, N(R')SO₂R', ureyl bearing 0-3 R', (C₅-Ci₀)aryl, (C₅-Ci₀)heteroaryl, (C₅- Ci₀)dihydroheteroaryl, (C₅-C i₀)tetrahydroheteroaryl, (C₃-Cio) mono- or bicyclic cycloalkyl, or (C₃-C io)mono- or bicyclo-heterocyclyl, wherein each R¹ independently comprises hydrogen, aryl or (Ci-C₆)alkyl wherein any aryl or alkyl can be substituted with 0-3 Y groups, or where two R¹ groups taken together with a nitrogen atom to which they are attached form together with the nitrogen atom a heterocyclic ring comprising 0-2 additional heteroatoms, substituted with 0-3 Y groups; wherein when any Y is an alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, dihydroheteroaryl, tetrahydroheteroaryl, cycloalkyl or heterocyclyl group, Y may be further substituted by 0-3 Y; or a salt, tautomer, solvate, hydrate, or a prodrug thereof.

2. The compound of claim 1 where Ar¹ is phenyl substituted with 0-3 Y groups.

3. The compound of claim 2 wherein Y is independently alkyl or halo.

4. The compound of claim 2 wherein Ar¹ is 2-chloro-6-methylphenyl.

5. The compound of claim 1 where Ar² is independently selected from phenyl, pyridinyl, or pyrimidinyl, substituted with 0-3 Y groups.

6. The compound of claim 5 wherein the pyrimidyl is 2-methyl-pyrimid-4-yl.

7. The compound of claim 5 wherein the pyridyl is 2-pyridyl.

8. The compound of claim 5 wherein Ar² comprises phenyl.

9. The compound of claim 1 wherein Ar² comprises 2-methyl-pyrimid-4-yl bearing a Y group at the 6-position.

10. The compound of claim 1 wherein X is NH.

11. The compound of claim 1 wherein X is N-(Ci -C₆)alkyl.

12. The compound of claim 1 wherein Ar² comprises

wherein a wavy line signifies a point of attachment; R³ and R⁴ each independently H, (Ci-C₆)alkyl, (C₃-Cg)mono- or bicyclic cycloalkyl, (C₃-C₈)mono-or bicyclic heterocyclyl, aryl, or heteroaryl; wherein any alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-3 Y; and wherein X¹ and X² are independently at each occurrence N or CR'.

13. The compound of claim 12 wherein X and X are N.

14. The compound of claim 12 or 13 wherein R³ is methyl.

15. The compound of claim 1 wherein R 1 o __r r R»2 , or both, are H

16. The compound of claim 1 comprising a compound of formula:

or

17. A method of inhibiting a protein kinase, in vitro or in vivo, comprising combining a compound selected from any one of claims 1-16 at an effective concentration with the protein kinase.

18. The method of claim 17 where the protein kinase is an Src kinase, including Src, Fyn, Lyn, Yes, or Lck kinase, or an AbI kinase.

19. A method of treating a mal condition in a mammal that is mediated by abnormal protein kinase activities, comprising administration of the compound of any one of claims 1-16 in a dosage, at a frequency, and for a duration to produce a beneficial effect on the patient.

20. The method of claim 19 wherein the protein kinase is an Src kinase, including Src, Fyn, Lyn, Yes, or Lck kinase, or an AbI kinase.

21. The method of claim 19 wherein the mal condition comprises cancer.

22. A pharmaceutical composition comprising a compound of any one of claims 1-16 and a suitable excipient.

23. A pharmaceutical combination comprising a compound of any one of claims 1-16 and a second medicament.

24. A method of use of the combination of claim 23 for treatment of a malcondition in a mammal that is mediated by abnormal protein kinase activities, comprising administration of the compound of any one of claims 1-16 and the second medicament in a dosage, at a frequency, and for a duration to produce a beneficial effect on the patient.

25. The method of claim 24 wherein the mal condition comprises cancer.

26. A method of preparing a compound of formula (I) of claim 1, comprising contacting a compound of formula (II):

(H), wherein L is a leaving group, and a boronate compound of formula (III):

Z-B(OR⁵)₂, wherein Z comprises an aryl or a heteroaryl group substituted with 0-3 Y groups; wherein R⁵ is H, an alkyl group, a boronate protecting group, or wherein two R⁵ groups taken together form a diester of the boronate compound; in the presence of a palladium complex, for sufficient time and at a sufficient temperature to provide a product of formula (I):

(I)-

27. The method of claim 25 wherein L is halo.

28. The method of claim 27 wherein the halo is chloro.

29. The method of claim 25 wherein the palladium complex is PdCl₂(PPh₃)₂ or Pd(PPh₃),.

30. The method of claim 25 wherein R⁵ is H.

31. The method of claim 25 wherein two R⁵ groups taken together comprise a terpene diol moiety.

32. A method of preparing a compound of formula (I) of claim 1, comprising contacting a compound of formula (II):

(H), wherein L is a leaving group, and a sodium alkoxide compound of formula (IV):

NaOZ¹ wherein Z' comprises a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl residue, wherein any carbon or nitrogen atom can bear a Y group; in tetrahydrofuran solution, for sufficient time and at a sufficient temperature to provide a product of formula (I):

(I)-