Deoxycytidine kinase inhibitors

Abstract

The present invention relates to compounds of formula (I) as deoxycytidine kinase inhibitors, and to pharmaceutical compositions comprising same. The present invention further relates to the use of such compounds of formula (I) for use in the treatment of cancer.

Description

[Technical Field]

[0001] The present invention relates to the field of medicine, in particular to deoxycytidine kinase (dCK) inhibitors and their use to treat cancer. [Background technology]

[0002] Deoxycytidine kinase (dCK) is an enzyme that plays a crucial role in cell division. This enzyme enables the phosphorylation of numerous deoxyribonucleosides and their nucleoside analogs. More specifically, dCK catalyzes the 5'-phosphorylation of physiological pyrimidines and purines, such as 2'-deoxycytosine (dC), 2'-deoxyadenosine (dA), and 2'-deoxyguanosine (dG). dCK has been observed to be predominantly expressed in a large panel of human cancer models in the Cancer Cell Line Encyclopedia (https: / / portals.broadinstitute.org / ccle) and has been associated with certain forms of resistance to antiviral and anticancer chemotherapeutic agents. In this context, dCK has been validated as an interesting target in oncology. Currently, there remains a need to develop additional dCK inhibitors for treating diseases and disorders in which dCK activity is implicated, such as cell proliferative disorders, particularly cancer. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Cancer Cell Line Encyclopedia(https: / / portals.broadinstitute.org / ccle) [Non-patent document 2] J. Pharm. Sci. 1977, 66, 2 [Non-patent document 3] Handbook of Pharmaceutical Salts: Properties, Selection, and Use, edited by P. Heinrich Stahl and Camille G. Wermuth, 2002 Summary of the Invention [Problem to be solved by the invention]

[0004] In this context, the inventors have obtained new compounds that have the property of binding to dCK and inhibiting its activity, thereby demonstrating the therapeutic interest of such compounds in medicine, more particularly in cancer therapy. [Means for solving the problem]

[0005] The present invention therefore provides a compound of formula (I)

[0006] [ka]

[0007] (In the formula, Y and Z independently represent NH, N, O, or S; R1, R2 and R3 independently represent a radical selected from the group consisting of hydrogen, -NR7R8 radicals (R7 and R8 are independently hydrogen or a (C1-C6) alkyl radical) and halogen; R4 and R5 are independently hydrogen, cycloalkyl, and -NR9R 10 Groups (R and R 10 are independently hydrogen or a (C1-C6) alkyl group, optionally substituted with a group selected from the group consisting of: R4 and R5 together form azepanyl; R6 represents hydrogen or halogen; X1 represents an -NHCO- group, an oxygen atom, a halogen atom, a -C≡C- group, or an -O-CH2- group; X2 represents a 5- to 12-membered ring optionally substituted with at least one group selected from the group consisting of a (C1-C6) alkyl group optionally substituted with at least one halogen, a (C1-C6) alkoxy group optionally substituted with at least one halogen, halogen, and hydroxy; X3 is (C1-C6) alkyl substituted by at least one A group, (C1-C6)alkoxy substituted by at least one A group, -C(O)- substituted by at least one A group, -SO2- substituted by at least one A group, -NH-SO2- substituted by at least one A group, -NHCO- substituted by at least one A group, wherein at least one of said A groups is piperazinyl optionally substituted by (C1-C6)alkyl or by (C1-C6)alkyl substituted by —COOH, -CO-piperazinyl substituted by (C1-C6) alkyl, - morpholinyl, piperidinyl optionally substituted with a -NR7R8 group, where R7 and R8 are independently hydrogen or a (C1-C6) alkyl group; or 2,6-diazaspiro[3.3]heptanyl substituted with (C1-C6)alkyl, -NR 11 R 12 Group(R 11 and R 12 are independently hydrogen, a (C1-C6) alkyl group, or a -SO2-CH3 group, - -NH-(C1-C6)alkyl-NR 13 R 14 Group(R 13 and R 14 are independently hydrogen or a (C1-C6) alkyl group, - (C1-C6)alkoxy, and - Hydroxy selected from the group consisting of Hydroxy, and -NR 15 R 16 Group(R 15 and R 16 are independently hydrogen or a (C1-C6) alkyl group. represents a group selected from the group consisting of n1, n2, and n3 are independently 0 or 1. and pharmaceutically acceptable salts, tautomers and solvates thereof.

[0008] In certain embodiments, compounds of formula (I), and pharmaceutically acceptable salts, tautomers, and solvates thereof, are as follows: Y and Z independently represent NH, N, O, or S; R1, R2 and R3 independently represent a radical selected from the group consisting of hydrogen, -NR7R8 radicals (R7 and R8 are independently hydrogen or a (C1-C6) alkyl radical) and halogen; R4 and R5 are independently hydrogen, cycloalkyl, and -NR9R 10 Groups (R and R 10 are independently hydrogen or a (C1-C6) alkyl group, optionally substituted with a group selected from the group consisting of: R4 and R5 together form azepanyl; R6 represents hydrogen or halogen; X1 represents an -NHCO- group, an oxygen atom, a -C≡C- group, or an -O-CH2- group; X2 represents a 5- to 12-membered ring optionally substituted with at least one group selected from the group consisting of a (C1-C6) alkyl group optionally substituted with at least one halogen, a (C1-C6) alkoxy group optionally substituted with at least one halogen, and a halogen; X3 is (C1-C6) alkyl substituted by at least one A group, (C1-C6)alkoxy substituted by at least one A group, -C(O)- substituted by at least one A group, -SO2- substituted by at least one A group, -NH-SO2- substituted by at least one A group, -NHCO- substituted by at least one A group, wherein at least one of said A groups is piperazinyl optionally substituted by (C1-C6)alkyl or by (C1-C6)alkyl substituted by —COOH, -CO-piperazinyl substituted by (C1-C6) alkyl, - morpholinyl, piperidinyl optionally substituted with a -NR7R8 group, where R7 and R8 are independently hydrogen or a (C1-C6) alkyl group; or 2,6-diazaspiro[3.3]heptanyl substituted with (C1-C6)alkyl, -NR 11 R 12 Group(R 11 and R 12 are independently hydrogen, a (C1-C6) alkyl group, or a -SO2-CH3 group, - -NH-(C1-C6)alkyl-NR 13 R 14 Group(R 13 and R 14 are independently hydrogen or a (C1-C6) alkyl group, - (C1-C6)alkoxy, and - Hydroxy selected from the group consisting of Hydroxy, and -NR 15 R 16 Group(R 15 and R 16are independently hydrogen or a (C1-C6) alkyl group. represents a group selected from the group consisting of n1, n2, and n3 are independently 0 or 1.

[0009] Preferably, the compound has the following formula (I'):

[0010] [ka]

[0011] (wherein R1, R2, R3, R4, R5, R6, X1, X2, X3, n1, n2, and n3 are, for example, as defined herein.) It has.

[0012] In certain embodiments, the compounds of formula (I) or (I') are such that at least one group selected from R1, R2, and R3 is not hydrogen.

[0013] In certain embodiments, the compound of formula (I) or (I') is as follows: R1 represents a -NR7R8 group (R7 and R8 are hydrogen), R2 represents hydrogen or halogen, preferably hydrogen; R3 represents hydrogen or a -NR7R8 group (R7 and R8 are hydrogen), preferably a -NR7R8 group (R7 and R8 are hydrogen).

[0014] In certain embodiments, the compound of formula (I) or (I') is as follows: R4 is hydrogen, cycloalkyl, or -NR9R 10 Groups (R and R 10 is hydrogen), preferably R4 represents a (C1-C6) alkyl group; R5 represents a (C1-C6) alkyl group, preferably a methyl group.

[0015] In certain embodiments, compounds of formula (I) or (I') are such that R6 represents hydrogen.

[0016] In certain embodiments, compounds of formula (I) or (I') are such that n1 + n2 + n3 is equal to or greater than 1, and preferably n1 + n2 + n3 is 1, 2, or 3.

[0017] In certain embodiments, compounds of formula (I) or (I') are such that n1 is 0.

[0018] In a further particular embodiment, the compound of formula (I) or (I') is such that n1 is 1 and X1 represents a -NHCO- group.

[0019] In certain embodiments, compounds of Formula (I) or (I') are such that n2 is 1 and X2 represents a 5-12 membered ring selected from the group consisting of phenyl, pyrimidinyl, thiophenyl, pyridinyl, triazolyl, and indolyl, wherein the 5-12 membered ring is optionally substituted with at least one group selected from the group consisting of methoxy, trifluoromethoxy, halogen, hydroxy, methyl, and trifluoromethyl.

[0020] In certain embodiments, compounds of formula (I) or (I') are such that n3 is 1 and X3 represents a group selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, -C(O)-, -SO2-, -NH-SO2- and -NHCO-, which is substituted by piperazinyl optionally substituted with (C1-C6)alkyl, preferably piperazinyl substituted with methyl.

[0021] In further particular embodiments, compounds of formula (I) or (I') are such that n3 is 1 and X3 represents at least one A group as defined herein, preferably piperazinyl substituted with methyl, -N(CH3)2, 2,6-diazaspiro[3.3]heptanyl substituted with methyl, and (C1-C6)alkyl substituted with -NHSO2CH3.

[0022] In further particular embodiments, compounds of formula (I) or (I') are those in which n3 is 1 and X3 is piperazinyl, -NR substituted with at least one A group as defined herein, preferably methyl. 11 R 12 Group(R 11 and R 12 are independently hydrogen or a methyl group) and morpholinyl.

[0023] In a preferred embodiment, the compound of formula (I) or (I') is as follows: R1, R2 and R3 independently represent hydrogen or a -NR7R8 group (R7 and R8 are independently hydrogen), preferably R1 and R3 represent NH2 and R2 represents H; R4 and R5 independently represent a (C1-C6) alkyl group, preferably R4 represents propyl and R5 represents methyl; R6 represents hydrogen; X2 represents a 5- to 6-membered ring selected from the group consisting of phenyl and pyridinyl, and the 5- to 6-membered ring is optionally substituted with at least one group selected from the group consisting of trifluoromethyl, trifluoromethoxy, halogen, hydroxy, methoxy, and methyl; X3 represents -SO2- substituted by at least one group selected from the group consisting of piperazinyl optionally substituted by (C1-C6)alkyl or (C1-C6)alkyl substituted by -COOH, piperidinyl optionally substituted by -NH2, and -NH-(C1-C6)alkyl-NH2; n1 is 0, n2 and n3 are 1.

[0024] Preferred compounds of formula (I) are - N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide dCKi-1; - N-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide dCKi-2: - N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide OR0105; - N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)-2-((4-methylpiperazin-1-yl)methyl)pyrimidine-5-carboxamide OR0125; - 4-(4-aminopyrimidin-2-yl)-N-(2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)phenoxy)phenyl)thiazol-2-amine OR0143; - N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-4-(2-(4-methylpiperazin-1-yl)ethyl)benzamide OR0146; - 4-(4-aminopyrimidin-2-yl)-N-(2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)phenyl)ethynyl)phenyl)thiazol-2-amine OR0153; - N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-4-((dimethylamino)methyl)benzamide OR0155; - N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-4-((6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)benzamide OR0156; - 4-(4-aminopyrimidin-2-yl)-N-(2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)benzyloxy)phenyl)thiazol-2-amine OR0232; - 4-(4-aminopyrimidin-2-yl)-N-(5-((4-((dimethylamino)methyl)phenyl)ethynyl)-2-methylphenyl)thiazol-2-amine OR0237; - N-(3-((4-(4-amino-5-fluoropyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide OR0239; - N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-5-((4-methylpiperazin-1-yl)methyl)thiophene-2-carboxamide OR0241; - 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-3-yl)thiazol-2-amine OR0274; - N-(1-(4-(4-aminopyrimidin-2-yl)thiazol-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide OR0289; - 3'-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4'-methyl-[1,1'-biphenyl]-4-ol OR0320; - 3'-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4'-methyl-[1,1'-biphenyl]-4-ol OR0321; - 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)thiazol-2-amine OR0325; - 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-(3-(4-methylpiperazin-1-yl)propyl)-[1,1'-biphenyl]-3-yl)thiazol-2-amine OR0331; - 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-(3-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)-N-propylthiazol-2-amine OR0345; - 2-(2-(8-(4-(2-(4-methylpiperazin-1-yl)ethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)thiazol-4-yl)pyrimidin-4-amine OR0402; - 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethoxy)-[1,1'-biphenyl]-3-yl)-N-propylthiazol-2-amine OR0596; - 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy)-[1,1'-biphenyl]-3-yl)-N-propylthiazol-2-amine OR0597; - 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-(3-(4-methylpiperazin-1-yl)propyl)-[1,1'-biphenyl]-3-yl)-N-propylthiazol-2-amine OR0598; - 4-(4-aminopyrimidin-2-yl)-N-(2-methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethyl)pyridin-3-yl)phenyl)-N-propylthiazol-2-amine OR0599; - 2-(2-((4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0600; - 2-(2-((4-methyl-4'-(3-(4-methylpiperazin-1-yl)propyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0601; - 2-(2-((2-methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0602; - 2-(2-(iso-butyl(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0603; - 2-(2-((cyclopropylmethyl)(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0604; - 2-(2-(iso-pentyl(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0605; - 2-(2-(butyl(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0606; - 2-(2-((4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0607; - 2-(2-(iso-butyl(2-methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-3-yl)phenyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0608; - N-((1-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(isobutyl)amino)-4-methylphenyl)-1H-1,2,3-triazol-4-yl)methyl)methanesulfonamide OR0609; - 2-(2-((2-aminoethyl)(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0610; - 2-(2-((3-aminopropyl)(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0611; - 2-[2-({2-methyl-5-[6-(4-methyl-piperazin-1-ylcarbonyl)-pyridin-3-yl]-phenyl}-propyl-amino)-thiazol-4-yl]-pyrimidine-4,6-diamine OR0612; - 2-(2-((5-(2-aminopyrimidin-5-yl)-2-methylphenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0613; - 2-(2-((4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0614; - 3'-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4'-methyl-[1,1'-biphenyl]-4-sulfonamide OR0615; - N-(5-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)pyridin-2-yl)-4-methylpiperazine-1-carboxamide OR0616; - 2-(2-((4-methyl-4'-(morpholinosulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0617; - 3'-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-N,N,4'-trimethyl-[1,1'-biphenyl]-4-sulfonamide OR0618; - 2-(2-((4'-((dimethylamino)methyl)-4-methyl-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0619; - 2-(2-((2-methyl-5-(pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0620; - (5-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)pyridin-2-yl)(morpholino)methanone OR0621; - methyl 5-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)picolinate OR0622; - N-(5-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)pyridin-2-yl)-4-methylpiperazine-1-sulfonamide OR0625; - 2-(2-((5-(1H-indol-5-yl)-2-methylphenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0626; - 2-(2-((2-methyl-5-(6-((4-methylpiperazin-1-yl)sulfonyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0627; - 2-(2-((2-methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0629; - 2-((5-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)pyridin-2-yl)oxy)-1-(4-methylpiperazin-1-yl)ethan-1-one OR0630; - 2-(2-(methyl(4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0631; - 2-(2-(ethyl(4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-di-amine OR0632; - 2-(2-((5-fluoro-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0633; - 2-(2-((3'-methoxy-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0635; - 2-(2-(iso-propyl(4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0636; - 2-(2-(iso-butyl(4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0637; - 2-(2-((4'-((4-ethylpiperazin-1-yl)sulfonyl)-4-methyl-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0638; - 2-(2-((4-methyl-4'-(piperazin-1-ylsulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0639; - 2-(2-((4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)oxazol-4-yl)pyrimidine-4,6-diamine OR0640; - 2-(2-((2'-chloro-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0641; - 2-(2-((4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-2'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0642; - 2-(2-((2'-fluoro-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0643; - 2-(2-((2'-fluoro-6'-methoxy-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0644; - 2-(2-((2'-methoxy-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0645; - 2-(2-((4-methyl-4'-(piperidin-4-ylsulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0646; - 2-(2-((2',6'-difluoro-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0647; - 2-(2-((4'-((4-aminopiperidin-1-yl)sulfonyl)-4-methyl-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0648; - 2-(4-((3'-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4'-methyl-[1,1'-biphenyl]-4-yl)sulfonyl)piperazin-1-yl)acetic acid OR0649; - 2-(2-((4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-3'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0650; - N-(2-aminoethyl)-3'-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4'-methyl-[1,1'-biphenyl]-4-sulfonamide OR0651; - 2-(2-((2-methyl-5-(4-methyl-6-((4-methylpiperazin-1-yl)sulfonyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0652; - 2-(2-((5-bromo-2-methylphenyl)(isobutyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0637-1; - 2-(2-((5-bromo-2-methylphenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0652-1; - 2-(2-((2-methyl-5-(2-methyl-6-((4-methylpiperazin-1-yl)sulfonyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0653; - 2-(2-((5-(6-methoxy-4-(trifluoromethyl)pyridin-3-yl)-2-methylphenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0654; - 2-(2-((5-(6-hydroxy-4-(trifluoromethyl)pyridin-3-yl)-2-methylphenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0655; - 2-(2-((2-methyl-5-(6-((4-methylpiperazin-1-yl)sulfonyl)-4-(trifluoromethyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0656; 2-(2-((2-methyl-5-(6-((4-methylpiperazin-1-yl)sulfonyl)-2-(trifluoromethyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0657; and - 2-(2-((2-methyl-5-(6-(piperazin-1-ylsulfonyl)-2-(trifluoromethyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0658 is selected from the group consisting of:

[0025] A further object of the present invention is a compound as defined herein for use as a medicament.

[0026] A further object is a pharmaceutical composition comprising a compound as defined herein and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition further comprises an inhibitor of the de novo nucleotide biosynthetic pathway, in particular a ribonucleotide reductase inhibitor, preferably thymidine.

[0027] Another object of the present invention is a compound as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment of cancer, preferably a liquid cancer, more preferably acute lymphoblastic leukemia, even more preferably T-cell acute lymphoblastic leukemia. [Brief explanation of the drawings]

[0028] [Figure 1] This is a scheme for a strategy to simultaneously target deoxyribonucleotide triphosphate synthesis by simultaneously inhibiting the de novo and salvage pathways. A dCK inhibitor combined with an RNR inhibitor inhibits cancer cell proliferation because both pathways are simultaneously inhibited. dTTP is generated from exogenously added dT via TK1, which acts as an RNR inhibitor to reduce pyrimidines through allosteric regulation of the R1 subunit. (RNR: ribonucleotide reductase; TK: thymidine kinase; dCK: deoxycytidine kinase). [Figure 2] Figure 1 shows the effect of compounds of the invention on dCK thermostabilization (as determined by binding assay in a thermal shift assay) and cell proliferation assay (in the CCRF-CEM cell line in the presence of 200 μM dT and 1 μM dC). Grey squares represent compound OR0642. [Figure 3] FIG. 1 shows the effect of selected compounds of the invention on cell proliferation of CCRF-CEM cell line in the presence of dT (200 μM) and dC (1 μM). [Figure 4] FIG. 1 shows vehicle and drug administration schedules (vehicle, dT 1.5 g / Kg, OR0642 40 mg / Kg, and dT+OR0642) (once daily (QD) and twice daily (BID)) for CCRF-CEM leukemia-bearing mice. [Figure 5] Effect of treatment on quantification of whole body radiance in CCRF-CEM leukemia-bearing mice (bioluminescence). Mice were treated with vehicle (CTRL), dT, OR0642, or dT + OR0642. Arrows highlight the end of treatment. Data are presented as mean ± SEM. [Figure 6] Effect of treatment on quantification of whole body radiance in CCRF-CEM leukemia-bearing mice (bioluminescence) on day 21. Mice were treated with vehicle (CTRL), dT, OR0642, or dT + OR0642. Comparison of bioluminescence data on day 21 was performed using one-way ANOVA, Kruskal-Wallis test, and Dunn's multiple comparison test. (NI = uninjected mice). [Figure 7] Figure 2 shows the effect of treatment of CCRF-CEM leukemia-bearing mice on the hCD45 population in the blood as determined by flux cytometry on day 21. Mice were treated with vehicle (CTRL), dT, OR0642, or dT + OR0642. Comparisons of hCD45 populations were performed using one-way ANOVA, Kruskal-Wallis test, and Dunn's multiple comparison test. [Figure 8] Figure 1. Survival analysis of CCRF-CEM leukemia-bearing mice treated with vehicle (CTRL), dT, OR0642, or dT + OR0642. Arrows highlight the end of treatment. Median survival times were compared using the Log-Rank (Mantel-Cox) test. DETAILED DESCRIPTION OF THE INVENTION

[0029] definition According to the present invention, the following terms have the following meanings: Terms referred to herein with a prefix, e.g., C1-C6, can also be used with a fewer number of carbon atoms, e.g., C1-C2. For example, when the term C1-C6 is used, it means that the corresponding hydrocarbon chain can contain 1 to 6 carbon atoms, particularly 1, 2, 3, 4, 5, or 6 carbon atoms. For example, when the term C1-C3 is used, it means that the corresponding hydrocarbon chain can contain 1 to 3 carbon atoms, particularly 1, 2, or 3 carbon atoms.

[0030] The term "alkyl" refers to a saturated linear or branched aliphatic group. The term "(C1-C6) alkyl" more specifically refers to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, or hexyl.

[0031] The term "alkoxy" or "alkyloxy" corresponds to an alkyl group as defined above attached to the molecule by an -O- (ether) bond. (C1-C6)alkoxy includes methoxy or methyloxy, ethoxy or ethyloxy, propoxy or propyloxy, isopropoxy or isopropyloxy, butoxy or butyloxy, isobutoxy or isobutyloxy, pentoxy or pentyloxy, isopentoxy or isopentyloxy, and hexoxy or hexyloxy.

[0032] The term "3- to 20-membered ring" refers to a ring having from 3 to 20 atoms. Such terms include the term "5- to 12-membered ring" having from 5 to 12 atoms. The term "ring" refers to a mono-, bi-, or tricyclic ring that may be saturated or unsaturated and optionally contains at least one heteroatom. In particular, the term "ring" includes cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0033] The term "cycloalkyl" refers to a saturated or unsaturated monocyclic, bicyclic, or tricyclic alkyl group containing from 3 to 20, preferably from 5 to 12, carbon atoms. It also includes fused, bridged, or spiro-linked cycloalkyl groups. The term "cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0034] The term "heterocycloalkyl" refers to saturated or unsaturated cycloalkyl groups as defined above further containing at least one heteroatom, such as nitrogen, oxygen, or sulfur atom. It also includes fused, bridged, or spiro-linked heterocycloalkyl groups. Representative heterocycloalkyl groups include, but are not limited to, dioxolanyl, benzo[1,3]dioxolyl, azetidinyl, oxetanyl, pyrazolinyl, pyranyl, thiomorpholinyl, pyrazolidinyl, piperidyl, piperazinyl, 1,4-dioxanyl, imidazolinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, azepanyl, 2,6-diazaspiro[3.3]heptanyl, imidazolidinyl, morpholinyl, 1,4-dithianyl, pyrrolidinyl, oxozolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, and tetrahydrothiophenyl. In preferred embodiments, heterocycloalkyl groups are azepanyl, piperazinyl, morpholinyl, piperidinyl, and 2,6-diazaspiro[3.3]heptanyl.

[0035] The term "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon having 6 to 12 carbon atoms. For example, the term "aryl" includes phenyl, naphtalenyl, or anthracenyl. In a preferred embodiment, aryl is phenyl.

[0036] As used herein, the term "heteroaryl" refers to an aromatic monocyclic or polycyclic group containing 5 to 14 atoms and at least one heteroatom, such as a nitrogen, oxygen, or sulfur atom. As used herein, the term "heteroaryl" further includes "fused arylheterocycloalkyl" and "fused heteroarylcycloalkyl." The terms "fused arylheterocycloalkyl" and "fused heteroarylcycloalkyl" refer to a bicyclic group in which an aryl or heteroaryl, as defined above, is bonded by at least two carbons to a heterocycloalkyl or cycloalkyl, as defined above, respectively. In other words, the aryl or heteroaryl shares a carbon bond with the heterocycloalkyl or cycloalkyl.Examples of such monocyclic and polycyclic heteroaryl groups, fused arylheterocycloalkyls and fused arylcycloalkyls are pyridinyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, furazanyl, thiadiazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolinyl, indanyl, quinolinyl, isoquinolinyl, benzimidazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, triazinyl, thianthrenyl, benzofuranyl, dihydrobenzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, chromenyl, xanthenyl, phenoxanthinyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, indazolyl yl, purinyl, quinolidinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, indole In preferred embodiments, the heteroaryl group may be pyrimidinyl, thiophenyl, pyridinyl, triazolyl, or indolyl.

[0037] The term "halogen" corresponds to a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine or bromine atom, preferably fluorine or chlorine.

[0038] The expressions "a group substituted with" and "a group substituted with at least" mean that the group is substituted with one or several of the groups listed. For example, the expression "(C1-C6) alkyl substituted with at least one halogen, preferably fluorine" can include fluoromethyl (-CH2F), difluoromethyl (-CHF2), or trifluoromethyl (-CF3).

[0039] The term "optionally substituted" means that the group is unsubstituted or substituted with one or several of the groups listed.

[0040] "Tautomers" are isomeric compounds that differ only in the position of protons and electrons.

[0041] A "solvate" is a compound that further contains at least one molecule of a solvent. A "hydrate" is a compound that further contains at least one molecule of water. For example, if a compound contains one molecule of water, it corresponds to a monohydrate form. If a compound contains two molecules of water, it corresponds to a dihydrate form.

[0042] "Pharmaceutical salts" include inorganic and organic acid salts. Representative examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, di- or trihydrochloric acid, di- or trihydrobromic acid, di- or trihydroiodic acid, di- or triphosphoric acid, etc. Representative examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, maleic acid, methanesulfonic acid, etc. Further examples of pharmaceutical inorganic or organic acid addition salts include the pharmaceutical salts listed in J. Pharm. Sci. 1977, 66, 2 and Handbook of Pharmaceutical Salts: Properties, Selection, and Use, edited by P. Heinrich Stahl and Camille G. Wermuth, 2002. In a preferred embodiment, the salt is selected from the group consisting of maleate, chlorhydrate, bromohydrate, and methanesulfonate. "Pharmaceutical salts" include inorganic as well as organic base salts. Representative examples of suitable inorganic bases include sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, or ammonium salts. Representative examples of suitable salts with organic bases include, for example, salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0043] -COR can refer to -C(O)-R, -CO- can refer to -C(O)-, -CONHR can refer to -C(O)-NH-R, -NRR' can refer to -N(R)R', -NHCO- can refer to -NH-CO-, -O-CH- can refer to -CH-O-, and -COR can refer to -C(O)-OR.

[0044] As used herein, the terms "treatment," "treat," or "treating" refer to any action intended to improve the health of a patient, e.g., the treatment, prevention, prophylaxis, and slowing of a disease, particularly cancer. In certain embodiments, such terms refer to the amelioration or eradication of the disease or symptoms associated therewith. In other embodiments, the terms refer to minimizing the spread or worsening of a disease resulting from the administration of one or more therapeutic agents to a subject with such a disease.

[0045] As used herein, the terms "subject," "individual," or "patient" are used interchangeably and refer to mammals, more preferably humans, including adults, children, newborns, and prenatal humans. However, the term "subject" can also refer to non-human animals, particularly mammals, such as dogs, cats, horses, cows, pigs, sheep, and non-human primates, among others.

[0046] The terms "quantity," "amount," and "dose" are used interchangeably herein and may refer to the absolute quantification of a molecule.

[0047] As used herein, the terms "active ingredient," "active ingredient," "drug substance," and "drug" are equivalent and refer to an ingredient of a pharmaceutical composition that has a therapeutic effect.

[0048] As used herein, the term "therapeutic effect" refers to an effect induced by an active ingredient or a pharmaceutical composition according to the present invention that can prevent or delay the onset or development of a disease or disorder, or cure or attenuate the effects of a disease or disorder.

[0049] As used herein, the term "effective amount" refers to the quantity of active ingredient or pharmaceutical composition that prevents, eliminates, or reduces the harmful effects of a disease, particularly cancer. It is clear that the quantity to be administered can be adapted by those skilled in the art depending on the subject to be treated, the nature of the disease, etc. In particular, the dosage and administration regimen can be a function of the nature, stage, and severity of the disease to be treated, as well as the weight, age, and general health of the subject to be treated, and the judgment of the physician.

[0050] As used herein, the term "pharmaceutically acceptable excipient" refers to any ingredient, other than the active ingredient, present in a pharmaceutical composition. Its addition may be for the purpose of imparting a particular consistency or other physical or taste properties to the final product. A pharmaceutically acceptable excipient must avoid any interactions, particularly chemical interactions, with the active ingredient.

[0051] compound The present invention provides new compounds of therapeutic interest.

[0052] According to the present invention, compounds, and pharmaceutically acceptable salts, tautomers and solvates thereof, are represented by the following formula (I):

[0053] [ka]

[0054] (In the formula, Y and Z independently represent NH, N, O, or S; R1, R2 and R3 independently represent a radical selected from the group consisting of hydrogen, -NR7R8 radicals (R7 and R8 are independently hydrogen or a (C1-C6) alkyl radical) and halogen; R4 and R5 are independently hydrogen, cycloalkyl, and -NR9R 10 Groups (R and R 10are independently hydrogen or a (C1-C6) alkyl group, optionally substituted with a group selected from the group consisting of: R4 and R5 together form azepanyl; R6 represents hydrogen or halogen; X1 represents an -NHCO- group, an oxygen atom, a halogen atom, a -C≡C- group, or an -O-CH2- group; X2 represents a 5- to 12-membered ring optionally substituted with at least one group selected from the group consisting of a (C1-C6) alkyl group optionally substituted with at least one halogen, a (C1-C6) alkoxy group optionally substituted with at least one halogen, halogen, and hydroxy; X3 is (C1-C6) alkyl substituted by at least one A group, (C1-C6)alkoxy substituted by at least one A group, -C(O)- substituted by at least one A group, -SO2- substituted by at least one A group, -NH-SO2- substituted by at least one A group, -NHCO- substituted by at least one A group, wherein at least one of said A groups is piperazinyl optionally substituted by (C1-C6)alkyl or by (C1-C6)alkyl substituted by —COOH, -CO-piperazinyl substituted by (C1-C6) alkyl, - morpholinyl, piperidinyl optionally substituted with a -NR7R8 group, where R7 and R8 are independently hydrogen or a (C1-C6) alkyl group; or 2,6-diazaspiro[3.3]heptanyl substituted with (C1-C6)alkyl, -NR 11 R 12 Group(R 11 and R12 are independently hydrogen, a (C1-C6) alkyl group, or a -SO2-CH3 group, - -NH-(C1-C6)alkyl-NR 13 R 14 Group(R 13 and R 14 are independently hydrogen or a (C1-C6) alkyl group, - (C1-C6)alkoxy, and - Hydroxy selected from the group consisting of Hydroxy, and -NR 15 R 16 Group(R 15 and R 16 are independently hydrogen or a (C1-C6) alkyl group. represents a group selected from the group consisting of n1, n2, and n3 are independently 0 or 1. It has.

[0055] According to particular embodiments of the present invention, the compound, and pharmaceutically acceptable salts, tautomers and solvates thereof, has the following formula (I):

[0056] [ka]

[0057] (In the formula, Y and Z independently represent NH, N, O, or S; R1, R2 and R3 independently represent a radical selected from the group consisting of hydrogen, -NR7R8 radicals (R7 and R8 are independently hydrogen or a (C1-C6) alkyl radical) and halogen; R4 and R5 are independently hydrogen, cycloalkyl, and -NR9R 10 Groups (R and R 10 are independently hydrogen or a (C1-C6) alkyl group, optionally substituted with a group selected from the group consisting of: R4 and R5 together form azepanyl; R6 represents hydrogen or halogen; X1 represents an -NHCO- group, an oxygen atom, a -C≡C- group, or an -O-CH2- group; X2 represents a 5- to 12-membered ring optionally substituted with at least one group selected from the group consisting of a (C1-C6) alkyl group optionally substituted with at least one halogen, a (C1-C6) alkoxy group optionally substituted with at least one halogen, and a halogen; X3 is (C1-C6) alkyl substituted by at least one A group, (C1-C6)alkoxy substituted by at least one A group, -C(O)- substituted by at least one A group, -SO2- substituted by at least one A group, -NH-SO2- substituted by at least one A group, -NHCO- substituted by at least one A group, wherein at least one of said A groups is piperazinyl optionally substituted by (C1-C6)alkyl or by (C1-C6)alkyl substituted by —COOH, -CO-piperazinyl substituted by (C1-C6) alkyl, - morpholinyl, piperidinyl optionally substituted with a -NR7R8 group, where R7 and R8 are independently hydrogen or a (C1-C6) alkyl group; or 2,6-diazaspiro[3.3]heptanyl substituted with (C1-C6)alkyl, -NR 11 R 12 Group(R 11 and R 12 are independently hydrogen, a (C1-C6) alkyl group, or a -SO2-CH3 group, - -NH-(C1-C6)alkyl-NR 13 R 14 Group(R13 and R 14 are independently hydrogen or a (C1-C6) alkyl group, - (C1-C6)alkoxy, and - Hydroxy selected from the group consisting of Hydroxy, and -NR 15 R 16 Group(R 15 and R 16 are independently hydrogen or a (C1-C6) alkyl group. represents a group selected from the group consisting of n1, n2, and n3 are independently 0 or 1. It has.

[0058] According to the invention, Y and Z independently represent NH, N, O or S. In particular, Y and Z independently represent N, O or S. In a preferred embodiment, Y represents N and Z represents O or S. In a more preferred embodiment, Y represents N and Z represents S. According to this more preferred embodiment, the compound has the following formula (I'):

[0059] [ka]

[0060] (wherein R1, R2, R3, R4, R5, R6, X1, X2, X3, n1, n2, and n3 are, for example, as defined herein.) It has.

[0061] According to the invention, R1, R2 and R3 independently represent a group selected from the group consisting of hydrogen, an -NR7R8 group (R7 and R8 are independently hydrogen or a (C1-C6) alkyl group) and halogen. In a particular embodiment, R1 represents hydrogen or an -NR7R8 group (R7 and R8 are hydrogen), i.e., an amino group -NH2, R2 represents hydrogen or a halogen, such as fluorine, preferably hydrogen, and R3 represents hydrogen or an -NR7R8 group (R7 and R8 are hydrogen), preferably an -NR7R8 group (R7 and R8 are hydrogen).

[0062] In certain embodiments, at least one group selected from R1, R2, and R3 is not hydrogen. In more particular embodiments, R1, R2, and R3 independently represent a group selected from the group consisting of hydrogen, a -NR7R8 group (R7 and R8 are independently hydrogen or a (C1-C6) alkyl group), and halogen, provided that at least one group selected from R1, R2, and R3 is not hydrogen. Preferably, R1 is not hydrogen. In preferred embodiments, R1 represents a -NR7R8 group (R7 and R8 are hydrogen), R2 represents hydrogen or halogen, preferably hydrogen, and R3 represents hydrogen or a -NR7R8 group (R7 and R8 are hydrogen), preferably a -NR7R8 group (R7 and R8 are hydrogen).

[0063] In a more preferred embodiment, R1 represents a -NR7R8 group (R7 and R8 are hydrogen), R2 represents hydrogen, and R3 represents a -NR7R8 group (R7 and R8 are hydrogen). According to this more preferred embodiment, R1 is -NH2, R2 is H, and R3 is -NH2.

[0064] According to the present invention, R and R are independently selected from hydrogen, cycloalkyl, and -NR 10 Groups (R and R 10 are independently hydrogen or a (C1-C6) alkyl group optionally substituted with a group selected from the group consisting of a (C1-C6) alkyl group, or R4 and R5 together form azepanyl.

[0065] In certain embodiments, R4 is hydrogen, or cycloalkyl, or -NR9R 10 Groups (R and R 10 is hydrogen). Preferably, R4 represents hydrogen, propyl, isopropyl, isobutyl, —CH2-cyclopropyl, isopentyl, butyl, —(CH2)2—NH2, —(CH2)3—NH2, methyl and ethyl, preferably propyl.

[0066] In a particular embodiment, R5 represents a (C1-C6) alkyl group, preferably a methyl group.

[0067] In more particular embodiments, R4 is hydrogen, or cycloalkyl, or -NR9R 10 Groups (R and R 10 is hydrogen), preferably, R4 represents a (C1-C6) alkyl group and R5 represents a (C1-C6) alkyl group, preferably a methyl group.

[0068] In a preferred embodiment, R4 represents a propyl group and R5 represents a methyl group.

[0069] In a further particular embodiment, R4 and R5 together form azepanyl.

[0070] According to the invention, R6 represents hydrogen or halogen. Preferably, R6 is hydrogen.

[0071] According to the present invention, n1, n2, and n3 are independently 0 or 1. In certain embodiments, n1 + n2 + n3 is equal to or greater than 1, and preferably n1 + n2 + n3 is 1, 2, or 3.

[0072] According to the present invention, n1 is 0 or 1. When n1 is 1, X1 represents an -NHCO- group, an oxygen atom, a halogen, a -C≡C- group or an -O-CH2- group. In a particular embodiment, n1 is 1 and X1 represents an -NHCO- group.

[0073] According to the present invention, n2 is 0 or 1. When n2 is 1, X2 represents a 5-12 membered ring optionally substituted with at least one group selected from the group consisting of a (C1-C6) alkyl group optionally substituted with at least one halogen, a (C1-C6) alkoxy group optionally substituted with at least one halogen, halogen, and hydroxy.

[0074] In certain embodiments, n2 is 1 and X2 represents a 5- to 12-membered ring selected from the group consisting of phenyl, pyrimidinyl, thiophenyl, pyridinyl, triazolyl, and indolyl, wherein the 5- to 12-membered ring is optionally substituted with at least one group selected from the group consisting of methoxy, trifluoromethoxy, halogen, hydroxy, methyl, and trifluoromethyl.

[0075] According to the present invention, n3 is 0 or 1. When n3 is 1, X3 is (C1-C6) alkyl substituted by at least one A group, (C1-C6)alkoxy substituted by at least one A group, -C(O)- substituted by at least one A group, -SO2- substituted by at least one A group, -NH-SO2- substituted by at least one A group, -NHCO- substituted by at least one A group, wherein at least one of said A groups is piperazinyl optionally substituted by (C1-C6)alkyl or by (C1-C6)alkyl substituted by —COOH, -CO-piperazinyl substituted by (C1-C6) alkyl, - morpholinyl, piperidinyl optionally substituted with a -NR7R8 group, where R7 and R8 are independently hydrogen or a (C1-C6) alkyl group; or 2,6-diazaspiro[3.3]heptanyl substituted with (C1-C6)alkyl, -NR 11 R 12 Group(R 11 and R 12 are independently hydrogen, a (C1-C6) alkyl group, or a -SO2-CH3 group, - -NH-(C1-C6)alkyl-NR 13 R 14 Group(R 13 and R 14 are independently hydrogen or a (C1-C6) alkyl group, - (C1-C6)alkoxy, and - Hydroxy selected from the group consisting of Hydroxy, and -NR 15 R 16 Group(R 15 and R 16 are independently hydrogen or a (C1-C6) alkyl group. represents a group selected from the group consisting of:

[0076] In certain embodiments, n3 is 1 and X3 represents a group selected from the group consisting of (C1-C6) alkyl, (C1-C6) alkoxy, -C(O)-, -SO2-, -NH-SO2- and -NHCO-, which is substituted by piperazinyl optionally substituted by (C1-C6) alkyl, preferably piperazinyl substituted by methyl.

[0077] In a particular embodiment, n1 is 1. According to this particular embodiment, X1 represents an -NHCO- group, an oxygen atom, a halogen, a -C≡C- group or an -O-CH2- group.

[0078] According to this particular embodiment, the compound of formula (I) or (I') is as follows: R1 is NH2, R2 is hydrogen or halogen, preferably fluorine; R3 is hydrogen or NH2; R4 is hydrogen or a (C1-C6) alkyl group, preferably propyl, and R5 represents a (C1-C6) alkyl group, preferably methyl, or R4 and R5 together form azepanyl; R6 represents hydrogen; X2 represents a 5- or 6-membered ring selected from the group consisting of phenyl, pyrimidinyl, and thiophenyl; X3 represents (C1-C6) alkyl substituted by at least one A group as defined herein, preferably piperazinyl substituted by methyl, -NH-(C1-C6) alkyl-NR 13 R 14 Group(R 13 and R 14 are independently hydrogen or methyl), and 2,6-diazaspiro[3.3]heptanyl substituted by methyl; n2 and n3 are 1.

[0079] In a preferred embodiment, n1 is 1 and X1 represents an -NHCO- group.

[0080] According to this preferred embodiment, the compound of formula (I) or (I') is as follows: R1 is NH2, R2 is hydrogen or halogen, preferably fluorine; R3 is hydrogen or NH2; R4 is hydrogen or a (C1-C6) alkyl group, preferably propyl, and R5 represents a (C1-C6) alkyl group, preferably methyl, or R4 and R5 together form azepanyl; R6 represents hydrogen; X2 represents a 5- or 6-membered ring selected from the group consisting of phenyl, pyrimidinyl, and thiophenyl; X3 represents (C1-C6) alkyl substituted by at least one A group as defined herein, preferably piperazinyl substituted by methyl, -NH-(C1-C6) alkyl-NR 13 R 14 Group(R 13 and R 14 are independently hydrogen or methyl), and 2,6-diazaspiro[3.3]heptanyl substituted by methyl; n2 and n3 are 1.

[0081] In a further preferred embodiment, n1 is 1 and X1 represents an oxygen atom.

[0082] According to this preferred embodiment, the compound of formula (I') is 4-(4-aminopyrimidin-2-yl)-N-(2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)phenoxy)phenyl)thiazol-2-amine OR0143.

[0083] In a preferred embodiment, n1 is 1 and X1 represents a halogen, preferably bromine. According to this preferred embodiment, the compounds of formula (I') are 2-(2-((5-bromo-2-methylphenyl)(isobutyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0637-1 and 2-(2-((5-bromo-2-methylphenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0652-1.

[0084] In a further preferred embodiment, n1 is 1 and X1 represents a -C≡C- group. R1 is NH2, R2 is hydrogen, R3 is hydrogen; R4 is hydrogen, R5 is a (C1-C6) alkyl group, preferably methyl; R6 represents hydrogen; X2 represents phenyl; X3 represents (C1-C6) alkyl substituted by at least one A group as defined herein, preferably piperazinyl substituted by methyl, -NH-(C1-C6) alkyl-NR 13 R 14 Group(R 13 and R 14 is independently selected from the group consisting of hydrogen or methyl; n2 and n3 are 1.

[0085] In a further preferred embodiment, n1 is 1 and X1 represents an -O-CH2- group.

[0086] According to this preferred embodiment, the compound of formula (I') is OR0232.

[0087] In a further detailed embodiment, n1 is 0.

[0088] According to this particular embodiment, n2 is 1 and X2 represents a 5- to 12-membered ring selected from the group consisting of phenyl, pyrimidinyl, thiophenyl, pyridinyl, triazolyl, and indolyl, said 5- to 12-membered ring being optionally substituted with at least one group selected from the group consisting of methoxy, trifluoromethoxy, halogen, hydroxy, methyl, and trifluoromethyl.

[0089] According to this particular embodiment, n3 is 0 or 1, preferably 1, and X3 represents a group selected from the group consisting of (C1-C6) alkyl, (C1-C6) alkoxy, -C(O)-, -SO2-, -NH-SO2- and -NHCO-, said group being substituted by at least one A group as defined herein.

[0090] In a preferred embodiment, n3 is 1 and X3 represents (C1-C6)alkyl substituted with at least one A group as defined herein. Preferably, said at least one A group is piperazinyl substituted with methyl, -N(CH3)2 and -NHSO2CH3.

[0091] In a further preferred embodiment, n3 is 1 and X3 represents -SO2- substituted by at least one A group as defined herein. Preferably, at least one said A group is piperazinyl, -NR2 optionally substituted by methyl, ethyl or -CH2-COOH. 11 R 12 Group(R 11 and R 12 are independently hydrogen or a methyl group), -NH-(CH2)2-NH2, morpholinyl, and piperidinyl optionally substituted with -NH2, more preferably piperazinyl unsubstituted or substituted with methyl, -NR 11 R 12 Group(R 11 and R 12 are independently hydrogen or a methyl group) or morpholinyl.

[0092] In a further preferred embodiment, n3 is 1 and X3 represents (C1-C6)alkoxy substituted with at least one A group as defined herein, preferably piperazinyl optionally substituted with methyl or —CO-piperazinyl optionally substituted with methyl.

[0093] In a further preferred embodiment, n3 is 1 and X3 represents -C(O)- substituted by at least one A group as defined herein, preferably piperazinyl optionally substituted by methyl, morpholinyl or methoxy.

[0094] In a further preferred embodiment, n3 is 1 and X3 represents -NH-SO2- substituted by at least one A group as defined herein, preferably piperazinyl optionally substituted by methyl.

[0095] In a further preferred embodiment, n3 is 1 and X3 represents -NHCO- substituted by at least one A group as defined herein, preferably piperazinyl optionally substituted by methyl.

[0096] In a further preferred embodiment, n3 is 1 and X3 represents hydroxy.

[0097] In a further preferred embodiment, n3 is 1 and X3 is -NR 15 R 16 Group(R 15 and R 16 are independently hydrogen or a (C1-C6) alkyl group, preferably methyl.

[0098] Preferred compounds of formula (I) or (I') are as follows: R1, R2 and R3 independently represent hydrogen or a -NR7R8 group (R7 and R8 are independently hydrogen), preferably with the proviso that at least one group selected from R1, R2 and R3 is not hydrogen. R4 and R5 independently represent hydrogen or a (C1-C6) alkyl group; R6 represents hydrogen; X1 represents an -NHCO- group; X2 represents a 5- to 6-membered ring selected from the group consisting of phenyl and pyridinyl, and the 5- to 6-membered ring is optionally substituted with at least one group selected from the group consisting of trifluoromethyl, trifluoromethoxy, halogen, hydroxy, methoxy, and methyl; X3 represents a group selected from the group consisting of (C1-C6) alkyl and -SO2-, and the group is substituted by piperazinyl substituted by (C1-C6) alkyl; n1 is 0 or 1, n2 and n3 are 1.

[0099] Further preferred compounds of formula (I) or (I') are as follows: R1, R2 and R3 independently represent hydrogen or a -NR7R8 group (R7 and R8 are independently hydrogen), preferably R1 and R3 represent NH2 and R2 represents H; R4 and R5 independently represent a (C1-C6) alkyl group, preferably R4 represents propyl and R5 represents methyl; R6 represents hydrogen; X2 represents a 5- to 6-membered ring selected from the group consisting of phenyl and pyridinyl, and the 5- to 6-membered ring is optionally substituted with at least one group selected from the group consisting of trifluoromethyl, trifluoromethoxy, halogen, hydroxy, methoxy, and methyl; X3 represents -SO2- substituted by at least one group selected from the group consisting of piperazinyl optionally substituted by (C1-C6)alkyl or (C1-C6)alkyl substituted by -COOH, piperidinyl optionally substituted by -NH2, and -NH-(C1-C6)alkyl-NH2; n1 is 0, n2 and n3 are 1.

[0100] Even more preferred compounds of formula (I) or (I') are as follows: R1 represents -NH2, R2 represents hydrogen, and R3 represents -NH2; R4 represents propyl and R5 represents methyl; R6 represents hydrogen; X2 represents phenyl optionally substituted with at least one group selected from the group consisting of trifluoromethyl, trifluoromethoxy, halogen, methoxy, and methyl; X3 represents -SO2- substituted by piperazinyl optionally substituted by methyl; n1 is 0, n2 and n3 are 1.

[0101] Particular compounds of formula (I) are - N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide dCKi-1; - N-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide dCKi-2: - N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide OR0105; - N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)-2-((4-methylpiperazin-1-yl)methyl)pyrimidine-5-carboxamide OR0125; - 4-(4-aminopyrimidin-2-yl)-N-(2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)phenoxy)phenyl)thiazol-2-amine OR0143; - N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-4-(2-(4-methylpiperazin-1-yl)ethyl)benzamide OR0146; - 4-(4-aminopyrimidin-2-yl)-N-(2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)phenyl)ethynyl)phenyl)thiazol-2-amine OR0153; - N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-4-((dimethylamino)methyl)benzamide OR0155; - N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-4-((6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)benzamide OR0156; - 4-(4-aminopyrimidin-2-yl)-N-(2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)benzyloxy)phenyl)thiazol-2-amine OR0232; - 4-(4-aminopyrimidin-2-yl)-N-(5-((4-((dimethylamino)methyl)phenyl)ethynyl)-2-methylphenyl)thiazol-2-amine OR0237; - N-(3-((4-(4-amino-5-fluoropyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide OR0239; - N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-5-((4-methylpiperazin-1-yl)methyl)thiophene-2-carboxamide OR0241; - 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-3-yl)thiazol-2-amine OR0274; - N-(1-(4-(4-aminopyrimidin-2-yl)thiazol-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide OR0289; - 3'-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4'-methyl-[1,1'-biphenyl]-4-ol OR0320; - 3'-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4'-methyl-[1,1'-biphenyl]-4-ol OR0321; - 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)thiazol-2-amine OR0325; - 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-(3-(4-methylpiperazin-1-yl)propyl)-[1,1'-biphenyl]-3-yl)thiazol-2-amine OR0331; - 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-(3-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)-N-propylthiazol-2-amine OR0345; - 2-(2-(8-(4-(2-(4-methylpiperazin-1-yl)ethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)thiazol-4-yl)pyrimidin-4-amine OR0402; - 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethoxy)-[1,1'-biphenyl]-3-yl)-N-propylthiazol-2-amine OR0596; - 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy)-[1,1'-biphenyl]-3-yl)-N-propylthiazol-2-amine OR0597; - 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-(3-(4-methylpiperazin-1-yl)propyl)-[1,1'-biphenyl]-3-yl)-N-propylthiazol-2-amine OR0598; - 4-(4-aminopyrimidin-2-yl)-N-(2-methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethyl)pyridin-3-yl)phenyl)-N-propylthiazol-2-amine OR0599; - 2-(2-((4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0600; - 2-(2-((4-methyl-4'-(3-(4-methylpiperazin-1-yl)propyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0601; - 2-(2-((2-methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0602; - 2-(2-(iso-butyl(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0603; - 2-(2-((cyclopropylmethyl)(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0604; - 2-(2-(iso-pentyl(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0605; - 2-(2-(butyl(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0606; - 2-(2-((4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0607; - 2-(2-(iso-butyl(2-methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-3-yl)phenyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0608; - N-((1-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(isobutyl)amino)-4-methylphenyl)-1H-1,2,3-triazol-4-yl)methyl)methanesulfonamide OR0609; - 2-(2-((2-aminoethyl)(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0610; - 2-(2-((3-aminopropyl)(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0611; - 2-[2-({2-methyl-5-[6-(4-methyl-piperazin-1-ylcarbonyl)-pyridin-3-yl]-phenyl}-propyl-amino)-thiazol-4-yl]-pyrimidine-4,6-diamine OR0612; - 2-(2-((5-(2-aminopyrimidin-5-yl)-2-methylphenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0613; - 2-(2-((4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0614; - 3'-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4'-methyl-[1,1'-biphenyl]-4-sulfonamide OR0615; - N-(5-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)pyridin-2-yl)-4-methylpiperazine-1-carboxamide OR0616; - 2-(2-((4-methyl-4'-(morpholinosulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0617; - 3'-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-N,N,4'-trimethyl-[1,1'-biphenyl]-4-sulfonamide OR0618; - 2-(2-((4'-((dimethylamino)methyl)-4-methyl-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0619; - 2-(2-((2-methyl-5-(pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0620; - (5-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)pyridin-2-yl)(morpholino)methanone OR0621; - methyl 5-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)picolinate OR0622; - N-(5-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)pyridin-2-yl)-4-methylpiperazine-1-sulfonamide OR0625; - 2-(2-((5-(1H-indol-5-yl)-2-methylphenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0626; - 2-(2-((2-methyl-5-(6-((4-methylpiperazin-1-yl)sulfonyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0627; - 2-(2-((2-methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0629; - 2-((5-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)pyridin-2-yl)oxy)-1-(4-methylpiperazin-1-yl)ethan-1-one OR0630; - 2-(2-(methyl(4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0631; - 2-(2-(ethyl(4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-di-amine OR0632; - 2-(2-((5-fluoro-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0633; - 2-(2-((3'-methoxy-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0635; - 2-(2-(iso-propyl(4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0636; - 2-(2-(iso-butyl(4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0637; - 2-(2-((4'-((4-ethylpiperazin-1-yl)sulfonyl)-4-methyl-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0638; - 2-(2-((4-methyl-4'-(piperazin-1-ylsulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0639; - 2-(2-((4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)oxazol-4-yl)pyrimidine-4,6-diamine OR0640; - 2-(2-((2'-chloro-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0641; - 2-(2-((4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-2'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0642; - 2-(2-((2'-fluoro-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0643; - 2-(2-((2'-fluoro-6'-methoxy-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0644; - 2-(2-((2'-methoxy-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0645; - 2-(2-((4-methyl-4'-(piperidin-4-ylsulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0646; - 2-(2-((2',6'-difluoro-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0647; - 2-(2-((4'-((4-aminopiperidin-1-yl)sulfonyl)-4-methyl-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0648; - 2-(4-((3'-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4'-methyl-[1,1'-biphenyl]-4-yl)sulfonyl)piperazin-1-yl)acetic acid OR0649; - 2-(2-((4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-3'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0650; - N-(2-aminoethyl)-3'-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4'-methyl-[1,1'-biphenyl]-4-sulfonamide OR0651; - 2-(2-((2-methyl-5-(4-methyl-6-((4-methylpiperazin-1-yl)sulfonyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0652; - 2-(2-((5-bromo-2-methylphenyl)(isobutyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0637-1; - 2-(2-((5-bromo-2-methylphenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0652-1; - 2-(2-((2-methyl-5-(2-methyl-6-((4-methylpiperazin-1-yl)sulfonyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0653; - 2-(2-((5-(6-methoxy-4-(trifluoromethyl)pyridin-3-yl)-2-methylphenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0654; - 2-(2-((5-(6-hydroxy-4-(trifluoromethyl)pyridin-3-yl)-2-methylphenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0655; - 2-(2-((2-methyl-5-(6-((4-methylpiperazin-1-yl)sulfonyl)-4-(trifluoromethyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0656; 2-(2-((2-methyl-5-(6-((4-methylpiperazin-1-yl)sulfonyl)-2-(trifluoromethyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0657; and - 2-(2-((2-methyl-5-(6-(piperazin-1-ylsulfonyl)-2-(trifluoromethyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0658 is selected from the group consisting of:

[0102] Purpose As illustrated by the examples, the inventors have demonstrated the therapeutic interest of the compounds of the present invention. Indeed, the inventors have shown that compounds according to the present invention are capable of binding to and inhibiting the activity of dCK, thereby demonstrating the therapeutic interest of such compounds in therapy, more particularly in cancer therapy. The inventors have also demonstrated that such compounds in combination with antitumor drugs, such as inhibitors of the de novo nucleotide biosynthetic pathway, significantly improved survival in a mouse leukemia model.

[0103] Accordingly, the present invention relates to a compound of formula (I) or (I') as defined herein for use as a medicament or medicine. The present invention further relates to a pharmaceutical or veterinary composition comprising a compound according to the present invention. Preferably, the pharmaceutical composition further comprises a pharmaceutically or veterinarily acceptable carrier or excipient. The present invention relates to the use of a compound according to the present invention as a medicament or medicine. The present invention further relates to a method for treating a disease in a subject, wherein a therapeutically effective amount of a compound according to the present invention is administered to said subject in need thereof. The present invention also relates to the use of a compound according to the present invention for the manufacture of a medicament. The present invention also relates to a pharmaceutical composition comprising a compound according to the present invention for use as a medicament.

[0104] The present invention provides a compound of formula (I) or (I') as defined above, including any one of the disclosed embodiments, or a pharmaceutical composition comprising such a compound, for preventing and / or treating cancer, or for use in the prevention and / or treatment thereof, and / or a pharmaceutical composition comprising a compound of formula (I) or (I') as defined above, including any one of the disclosed embodiments, and an antitumor agent for the prevention and / or treatment of cancer, or for use in the prevention and / or treatment of cancer, and / or a compound of formula (I) or (I') comprising any one of the disclosed embodiments, or a pharmaceutical composition comprising such a compound, for preventing and / or treating cancer, in combination with radiation therapy, hyperthermia and / or other anti-tumor therapy, optionally prior to, simultaneously with and / or after surgery (e.g., tumor resection), and / or for use in preventing and / or treating cancer; and / or - a kit comprising (a) a compound of formula (I) or (I') as defined above, including any one of the disclosed embodiments, and (b) an antitumor agent as a combined preparation, for simultaneous, separate or sequential use, for preventing and / or treating cancer, or for use in preventing and / or treating cancer; and / or - use of a compound of formula (I) or (I') as defined above, including any one of the disclosed embodiments, or a pharmaceutical composition comprising such a compound, for the manufacture of a medicament, drug or medicament for the prevention and / or treatment of cancer; and / or - use of a pharmaceutical composition comprising a compound of formula (I) or (I') as defined above, including any one of the disclosed embodiments, and an additional antitumor agent, for the manufacture of a medicament, drug or medicament for the prevention and / or treatment of cancer; and / or - use of a compound of formula (I) or (I') as defined above, including any one of the disclosed embodiments, or a pharmaceutical composition comprising such a compound, for the manufacture of a medicament, drug or medicament for the prevention and / or treatment of cancer, in combination with radiation therapy, hyperthermia and / or other anti-tumor therapies, optionally prior to, simultaneously with and / or after surgery (e.g. tumor resection); and / or - a method for treating cancer, comprising administering to a subject in need thereof an effective amount of a compound as defined herein of formula (I) or (I'), or a pharmaceutical composition comprising such a compound; - a method for treating cancer, comprising administering to a subject in need thereof an effective amount of a compound as defined herein of formula (I) or (I'), or a pharmaceutical composition comprising such a compound and an additional antitumor agent; - a method for treating cancer, comprising administering to a subject in need thereof an effective amount of a compound as defined herein of formula (I) or (I'), or a pharmaceutical composition comprising such a compound, optionally further comprising radiation therapy, hyperthermia and / or other anti-tumor therapy prior to, concurrent with and / or after surgery (e.g., tumor resection).

[0105] The term "cancer," as used herein, refers to the presence of cells that possess characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortalization, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features. Cancer can be a solid cancer, such as a solid tumor, or a liquid cancer, such as a hematopoietic tumor. Examples of cancer include, for example, leukemia, lymphoma, blastoma, carcinoma, including cholangiocarcinoma and sarcoma. More particular examples of such cancers include chronic myeloid leukemia, acute lymphoblastic leukemia, e.g., T-cell acute lymphoblastic leukemia, Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL), squamous cell carcinoma, lung cancer, small cell lung cancer, non-small cell lung cancer, glioma, gastrointestinal cancer, renal cancer, ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, melanoma, skin cancer, thyroid cancer, neuroblastoma, osteosarcoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, gastric cancer, bladder cancer, hepatoma, breast cancer, oesophageal cancer, colon cancer, head and neck cancer, brain cancer, stomach cancer, germ cell tumors, childhood sarcoma, sinonasal natural killer lymphoma, multiple myeloma, acute myeloid leukemia (AML), chronic lymphocytic leukemia, mastocytosis, and any condition associated with mastocytosis. In certain embodiments, the cancer is a liquid cancer, preferably acute lymphoblastic leukemia, more preferably T-cell acute lymphoblastic leukemia.

[0106] As used herein, the term "therapy" refers to any type of cancer treatment (i.e., anti-tumor therapy), including adjuvant and neoadjuvant therapy. Therapy includes radiation therapy, preferably systemic therapy, such as hormonal therapy, chemotherapy, immunotherapy, and monoclonal antibody therapy.

[0107] As used herein, the term "adjuvant therapy" refers to any type of cancer treatment administered as an additional treatment, usually after surgical resection of the primary tumor, in patients with cancer that is at risk of metastasis and / or prone to recurrence. The purpose of such adjuvant treatment is to improve prognosis. Adjuvant therapy includes radiation therapy, preferably systemic therapy, such as hormonal therapy, chemotherapy, immunotherapy, and monoclonal antibody therapy.

[0108] The term "hormonal therapy" or "hormonal therapy" refers to cancer treatments that aim to block, add, or remove hormones. For example, in breast cancer, the female hormones estrogen and progesterone can promote the growth of some breast cancer cells. Therefore, in these patients, hormone therapy is administered to block estrogen; a non-exhaustive list of commonly used drugs includes tamoxifen, toremifene, anastrozole, exemestane, letrozole, goserelin, leuprolide, megestrol acetate, and fluoxymesterone.

[0109] As used herein, the term "chemotherapeutic treatment" or "chemotherapy" refers to a cancer therapeutic treatment using chemical or biological agents, particularly using one or several anti-neoplastic agents.

[0110] The term "radiation therapy treatment" or "radiation therapy" is a term commonly used in the art to refer to multiple types of radiation therapy, including internal and external radiation therapy, or radioimmunotherapy, and the use of various types of radiation, including x-rays, gamma rays, alpha particles, beta particles, photons, electrons, neutrons, radioisotopes, and other forms of ionizing radiation.

[0111] The term "therapeutic antibody" refers to any antibody that has an anti-tumor effect.

[0112] Preferably, the therapeutic antibody is a monoclonal antibody. The therapeutic antibody is generally specific for a surface antigen, e.g., a membrane antigen. Most preferred therapeutic antibodies are tumor antigens (e.g., molecules specifically expressed by tumor cells), such as CD20, CD52, ErbB2 (or HER2 / Neu), CD33, CD22, CD25, MUC-1, CEA, KDR, aVb3, etc. Therapeutic antibodies include, but are not limited to, antibodies such as trastuzumab (anti-HER2 antibody), rituximab (anti-CD20 antibody), alemtuzumab, gemtuzumab, cetuximab, pertuzumab, epratuzumab, basiliximab, daclizumab, labetuzumab, cevirumab, tubulimab, palivizumab, infliximab, omalizumab, efalizumab, natalizumab, clenoliximab, and bevacizumab.

[0113] Hyperthermia is a medical procedure in which cancer cells are exposed to high temperatures to damage and kill them, or to make them more sensitive to the effects of radiation and certain anti-cancer drugs. There are many techniques by which heat can be delivered that are well known by those skilled in the art. Some of the most common involve the use of focused ultrasound (FUS or HIFU), infrared saunas, microwave heating, induction heating, electromagnetic wave hyperthermia, injection of warm liquids, or the direct application of heat, for example, by sitting in a warm room or wrapping the patient in a warm blanket.

[0114] The route of administration may be topical, transdermal, oral, rectal, sublingual, intranasal, intrathecal, intratumoral or parenteral (including subcutaneous, intramuscular, intravenous and / or intradermal). Preferably, the route of administration is parenteral, oral or topical. The pharmaceutical composition is adapted for one or several of the above-mentioned routes. The pharmaceutical composition, kit, product or combined preparation is preferably administered by injection, or by intravenous injection or a suitable sterile solution, or in the form of a liquid or solid dosage via the digestive tract.

[0115] Pharmaceutical compositions can be formulated as solutions in pharmaceutically compatible solvents, or as emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or vehicles, or as pills, tablets, or capsules containing a solid vehicle in any manner known in the art. Formulations of the present invention suitable for oral administration can be in the form of discrete units such as capsules, sachets, tablets, or lozenges, each containing a predetermined amount of the active ingredient in powder or granular form, in solution or suspension in an aqueous or non-aqueous liquid, or in the form of an oil-in-water or water-in-oil emulsion. Formulations for rectal administration can be in the form of suppositories incorporating the active ingredient and a carrier such as cocoa butter, or in the form of enemas. Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient, preferably isotonic with the blood of the recipient. All such formulations can also contain other pharmaceutically compatible and non-toxic auxiliary substances, such as stabilizers, antioxidants, binders, dyes, emulsifiers, or flavoring substances. The formulations of the present invention comprise the active ingredient together with a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof. The pharmaceutical composition is advantageously applied by infusion or intravenous injection of a suitable sterile solution, or by oral administration via the digestive tract. Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. Furthermore, their administration is described in standard literature.

[0116] The pharmaceutical composition according to the present invention can be formulated to release the active drug substantially immediately after administration or at any predetermined time or period after administration. Preferably, treatment with the compound according to the present invention or the pharmaceutical composition according to the present invention is started within one month, preferably within one week, after diagnosis of the disease. In the most preferred embodiment, treatment is started on the day of diagnosis.

[0117] The compounds according to the invention or the pharmaceutical compositions according to the invention may be administered as a single dose or in multiple doses.

[0118] Preferably, the treatment is administered periodically, preferably daily to monthly, more preferably daily to every two weeks, more preferably daily and weekly, and even more preferably, the treatment is administered daily. In certain embodiments, the treatment is administered several times a day, preferably two or three times a day, and even more preferably three times a day.

[0119] The duration of treatment using the compound according to the present invention or the pharmaceutical composition according to the present invention preferably includes 1 day to 50 weeks, more preferably 1 day to 30 weeks, even more preferably 1 day to 15 weeks, and even more preferably 1 day to 10 weeks. In certain embodiments, the duration of treatment is about 1 week. Alternatively, treatment may continue as long as the disease persists.

[0120] The amount of the compound according to the present invention or the pharmaceutical composition according to the present invention to be administered should be determined by standard procedures well known to those skilled in the art. The patient's physiological data (e.g., age, size, and weight) and the route of administration should be taken into consideration to determine the appropriate dosage so that a therapeutically effective amount is administered to the patient. In a preferred embodiment, the total compound dose for each administration of the compound according to the present invention or the pharmaceutical composition according to the present invention comprises 0.00001 to 1 g, preferably 0.01 to 10 mg. The form of the pharmaceutical composition, the route of administration and the dosage of the compound according to the present invention or the pharmaceutical composition according to the present invention can be adjusted by those skilled in the art according to the type and severity of the disease and the patient, in particular their age, weight, sex, and general physical condition.

[0121] Antitumor drugs In certain embodiments, the compounds of the present invention may be used in combination with another antitumor or anti-neoplastic agent. The additional antitumor agent may be selected from the non-exhaustive list of antitumor agents consisting of inhibitors of topoisomerase I or II, antimitotic agents, DNA alkylating agents, agents that cause DNA cross-linking, antimetabolites, targeting agents such as kinase inhibitors, histone deacetylase inhibitors, and anti-EGFR agents, and / or therapeutic antibodies designed to mediate cytotoxicity against cancer cells or to modulate one of their important biological functions.

[0122] Antimitotic agents include paclitaxel, docetaxel, and analogs such as larotaxel (also known as XRP9881, Sanofi-Aventis), XRP6258 (Sanofi-Aventis), BMS-184476 (Bristol-Meyer-Squibb), BMS-188797 (Bristol-Meyer-Squibb), BMS-275183 (Bristol-Meyer-Squibb), ortataxel (IDN 5109, also known as BAY 59-8862 or SB-T-101131, Bristol-Meyer-Squibb), RPR 109881A (Bristol-Meyer-Squibb), RPR 116258 (Bristol-Meyer-Squibb), NBT-287 (TAPESTRY), PG-paclitaxel (also known as CT-2103, PPX, paclitaxel poliglumex, paclitaxel polyglutamate or Xyotax™), ABRAXANE® (also known as Nab-paclitaxel, ABRAXIS BIOSCIENCE), tesetaxel (also known as DJ-927), IDN 5390 (INDENA), taxoplexin (also known as docosahexanoic acid-paclitaxel, PROTARGA), DHA-paclitaxel (also known as Taxoprexin®), and MAC-321 (WYETH). Preferably, the antimitotic agent is docetaxel, paclitaxel, more preferably docetaxel.

[0123] Inhibitors of topoisomerase I and / or II include, but are not limited to, etoposide, topotecan, camptothecin, irinotecan, amsacrine, intoplicin, anthracyclines such as doxorubicin, epirubicin, daunorubicin, idarubicin, and mitoxantrone. Inhibitors of topoisomerase I and II include, but are not limited to, intoplicin.

[0124] The additional antitumor agent may be an alkylating agent, including, but not limited to, nitrogen mustard, ethyleneimine derivatives, alkylsulfonates, nitrosoureas, metal salts, and triazenes. Non-exhaustive examples include uracil mustard, chlormethine, cyclophosphamide (CYTOXAN®), ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, cisplatin, carboplatin, fotemustine, oxaliplatin, thiotepa, streptozocin, dacarbazine, and temozolomide. In a preferred embodiment, the DNA alkylating agent is preferably cisplatin, carboplatin, temozolomide, fotemustine, or dacarbazine.

[0125] Antimetabolites block enzymes responsible for nucleic acid synthesis or become incorporated into DNA, producing an incorrect genetic code, leading to apoptosis. Non-exhaustive examples include, but are not limited to, antifolates, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors, more specifically methotrexate, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, 5-fluorouracil, gemcitabine, and capecitabine. In a preferred embodiment, such an agent is gemcitabine.

[0126] The additional antitumor agent may also be a targeting agent, specifically a kinase inhibitor. The kinase may be selected from the group consisting of intracellular tyrosine or serine / threonine kinases, receptor tyrosine or serine / threonine kinases. The kinase may be selected from the EGFR family, ALK, B-Raf, MEK, and mTOR. For example, the agent may have the ability to inhibit angiogenesis based on its inhibitory activity against VEGFR and PDGFR kinases. In particular, the targeted agent may be selected from several already approved kinase inhibitors: Gleevec®, which inhibits Bcr-Abl and c-Kit, and Iressa® and Tarceva®, both of which inhibit EGFR; sorafenib (Nexavar®, BAY 43-9006), which inhibits Raf; dasatinib (BMS-354825) and nilotinib (AMN-107, Tasigna®), which also inhibit Bcr-Abl; lapatinib, which also inhibits EGFR; temsirolimus (Torisel®, CCI-779), which targets the mTOR pathway; sunitinib (Student®, SU11248), which inhibits several targets including VEGFR; and specific antibodies that inactivate kinase receptors: Herceptin® and Avastin®. The anti-EGFR agent may be selected from gefitinib, erlotinib, lapatinib, vandetanib, afatinib, osimertinib, neratinib, dacomitinib, brigatinib, canertinib, nacotinib, nazartinib, pelitinib, rociletinib, icotinib, AZD3759, AZ5104 (CAS No. 1421373-98-9), poziotinib, and WZ4002, and is preferably erlotinib or cetuximab. The ALK inhibitor may be selected from crizotinib, entrectinib, ceritinib, alectinib, brigatinib, lorlatinib, TSR-011, CEP-37440, and ensartinib. The B-Raf inhibitor may be selected from vemurafenib, dabrafenib, regorafenib, and PLX 4720. The MEK inhibitor may be selected from cobimetinib, trametinib, binimetinib, selumetinib, PD-325901, CI-1040, PD035901, U0126, and TAK-733.

[0127] The additional drug may also be a checkpoint inhibitor, such as an antibody that targets PD-1, PD-L1, CTLA-4, or the like.

[0128] De Novo Pathway Inhibitors In a preferred embodiment, the compounds of the present invention can be used in combination with inhibitors of the de novo nucleotide biosynthetic pathway. In the de novo (ab initio) pathway, nucleotide bases are assembled from simpler compounds. The backbone of the pyrimidine base is first assembled and then attached to ribose. In contrast, the backbone of the purine base is synthesized one by one directly on a ribose-based structure. The de novo pathway synthesizes pyrimidine and purine nucleotides from amino acids, carbon dioxide, folic acid derivatives, and phosphoribosyl pyrophosphate (PRPP).

[0129] As used herein, the term "De Novo nucleotide biosynthetic pathway inhibitor," "inhibitor of a De Novo nucleotide biosynthetic pathway," or simply "De Novo pathway inhibitor" or "inhibitor of a De Novo pathway" refers to any agent (e.g., a compound, antibody, protein, or nucleic acid) that is capable of reducing the level of a protein component of a De Novo nucleotide biosynthetic pathway, the mRNA of a protein component of a De Novo nucleotide biosynthetic pathway, or the activity of a component of a De Novo nucleotide biosynthetic pathway compared to a control (e.g., compared to the level in the absence of a De Novo pathway inhibitor). Preferably, the De Novo pathway inhibitor is a compound (e.g., a molecule). The De Novo pathway inhibitor can reduce the level of production of dCTP and / or dATP and / or dGTP, and dTTP compared to a control (e.g., without a De Novo pathway inhibitor). Non-limiting examples of De Novo pathway inhibitors are listed below. - methotrexate, ((2S)-2-[(4-{[(2,4-diaminopteridin-6-yl)methyl](methyl)amino}benzoyl)amino]pentanedioic acid) (CAS number 59-05-2), - mercaptopurine (MP) (3,7-dihydropurine-6-thione) (CAS number 50-44-2), - 5-fluorouracil (5-FU) (CAS number 51-21-8, - mycophenolic acid (MPA) (CAS number 24280-93-1), - mizoribine (1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-hydroxyimidazole-4-carboxamide) (CAS number 50924-49-7), - teriflunomide ((Z)-2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]but-2-enamide) (CAS number 163451-81-8), - brequinar (6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic acid) (CAS number 96187-53-0), - Vidofludimus (2-[[2-fluoro-4-(3-methoxyphenyl)phenyl]carbamoyl]cyclopentene-1-carboxylic acid) (CAS number 717824-30-1), BAY 2402234 ((S)-N-(2-chloro-6-fluorophenyl)-4-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-((1,1,1-trifluoropropan-2-yl)oxy)benzamide) (CAS number 2225819-06-5), and - Leflunomide (5-methyl-N-[4-(trifluoromethyl)phenyl]-isoxazole-4-carboxamide) (CAS number: 75706-12-6).

[0130] In a more preferred embodiment, the inhibitor of the De Novo pathway is a ribonucleotide reductase (RNR) inhibitor. As used herein, the term "ribonucleotide reductase inhibitor" or "ribonucleotide reductase inhibitor" refers to an agent (e.g., a compound, antibody, protein, or nucleic acid) that can reduce the level of RNR protein, RNR mRNA, or RNR activity compared to a control (e.g., compared to the level without the RNR inhibitor). Preferably, the RNR inhibitor is a compound (e.g., a molecule). The RNR inhibitor can reduce the level of RNR activity. The RNR inhibitor can reduce the level of RNR activity when the RNR inhibitor binds to RNR. Non-limiting examples of RNR inhibitors are listed below. - hydroxycarbamide (CAS number 127-07-1), also known as hydroxyurea, - Motexafin gadolinium (CAS number: 156436-89-4), Fludarabine ((2R,3S,4S,5R)-2-(6-amino-2-fluoropurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol) (CAS number 21679-14-1), - cladribine (5-(6-amino-2-chloro-purin-9-yl)-2-(hydroxymethyl)oxolan-3-ol) (CAS number 4291-63-8), - gemcitabine (4-amino-1-(2-deoxy-2,2-difluoro-β-D-erythropentofuranosyl)pyrimidin-2(1H)-on) (CAS number 95058-81-4), Tezacitabine (4-amino-1-[(2R,3E,4S,5R)-3-(fluoromethylidene)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2(1H)-one) (CAS number 130306-02-4), - DMDC (deoxy-2'-methylidenecytidine) (CAS number 119804-96-5), - Cytarabine (cytosine arabinoside) (CAS Number (CAR Number) 147-94-4), - Triapine (3-aminopyridine-2-carbaldehyde thiosemicarbazone) (CAS number 236392-56-6), - Dp44mT (2-(di-2-pyridinylmethylene)-N,N-dimethyl-hydrazinecarbothioamide) (CAS number 152095-12-0), - DpT (di(2-pyridyl)ketone thiosemicarbazone) (CAS number 6839-91-4), - DpC (di-2-pyridyl ketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone hydrochloride) (CAS number 1382469-40-0), - Dp2mT (di-2-pyridylketone-2-methyl-3-thiosemicarbazone) (CAS number 741250-22-6), - Gallium maltolate (tris(3-hydroxy-2-methyl-4H-pyran-4-one)gallium) (CAS number 108560-70-9), - gallium nitrate (CAS number 13494-90-1), - clofarabine (5-(6-amino-2-chloro-purin-9-yl)-4-fluoro-2-(hydroxymethyl)oxolan-3-ol) (CAS number 123318-82-1), - Didox (3,4-dihydroxybenzohydroxamic acid) (CAS number 69839-83-4), - Trimidox (3,4,5-trihydroxybenzamidoxime) (CAS number 95933-74-7), - COH29 (N-(4-(3,4-dihydroxyphenyl)-5-phenylthiazol-2-yl)-3,4-dihydroxybenzamide) (CAS number 1190932-38-7), - DFOA (desferrioxamine) (CAS number 70-51-9), - PIH (pyridoxal isonicotinoyl hydrazone) (CAS number 737-86-0), and - thymidine (dT), also known as deoxythymidine, deoxyribosylthymine (1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4(1H,3H)-dione) (CAS number 50-89-5).

[0131] In an even more preferred embodiment, the ribonucleotide reductase inhibitor is thymidine.

[0132] Further aspects and advantages of the present invention are disclosed in the experimental section below. [Example]

[0133] Example A chemistry General Methods. Commercially available reagents and solvents were used without further purification. Thin-layer chromatography (TLC) was performed on silica pre-coated aluminum sheets (60 F254 nm, Merck) and visualized using short-wave UV light. Reaction monitoring and compound purity were monitored using DAD at 254 nm. Columns were Agilent Poroshell 120 EC-C18 2.7 μm (4.6 × 50 mm), mobile phase (A: 0.1% FA HO, B: 0.1% FA MeCN), method (A) flow rate 0.3 mL / min, time / %B 0 / 10, 4 / 90, 7 / 90, 9 / 10, 10 / 10; method (B) flow rate 0.5 mL / min, time / %B 0 / 10, 4 / 90, 7 / 90, 9 / 10, 13 / 10; mobile phase (A: 0.1% TFA HO, B: 0.1% TFA MeCN), method (C) flow rate 1 mL / min, time / %B 0 / 10, 5 / 100, 8 / 100; column Thermo Scientific Hypersil Gold. The data were recorded using an analytical Agilent Infinity high-performance liquid chromatograph (HPLC) with a 12 μm column (4.6 × 250 mm) and mobile phase (A: 0.1% TFA HO, B: 0.1% TFA MeCN) at a flow rate of 2 mL / min, with time / %B ratios of 0 / 10, 6 / 100, and 11 / 100. Column chromatography was performed on a Revelis flash silica cartridge or a Revelis purification system using a C18 40 μM cartridge. The petroleum fraction refers to the fraction distilled between 40 and 65 °C. 1 H and 13 C NMR spectra were recorded using a Bruker AC 400, AC 300, or AC 250 spectrometer. Chemical shifts (δ) are reported in ppm and coupling values ​​(J) in Hertz. Peak abbreviations are: br: broad, s: singlet, d: doublet, t: triplet, q: quartet, quint: quintet, sext: sextet, sept: septet, and m: multiplet. The recorded spectra are consistent with the proposed structures. Low-resolution mass spectra were obtained using an Agilent SQ G6120B mass spectrometer in positive and negative electrospray mode.

[0134] General methods for preparing compounds of the present invention are illustrated by Schemes 1-7.

[0135] [ka]

[0136] Reagents and conditions: i) BocO, DMAP; ii) tributyl(1-ethoxyvinyl)tin, Pd(PPh)Cl, CsF, CuBr; iii) NBS; iv) KSCN, AcCl; v) KCO, EtOH; vi) KCO, EtOH; vii) optionally NaH, RBr; viii) Zn, AcOH, or SnCl 2. 2H2O, EtOH; ix) HATU, DIPEA; x) TFA.

[0137] N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-aryl)benzamide derivatives were prepared by a convergent synthesis from commercially available 4-amino-2-chloropyrimidine and the appropriate nitroaniline (Scheme 1). 4-Amino-2-chloropyrimidine was protected using BocO to give the corresponding bis-carbamate. Stille cross-coupling reaction with tributyl(1-ethoxyvinyl)tin gave the enol ether, which was then converted to the corresponding α-bromoketone using N-bromosuccinimide. Starting from the appropriate nitroaniline, condensation with acetylisothiocyanate followed by saponification gave the corresponding thiourea. The α-bromoketone was used with thiourea in the Hantzsch thiazole synthesis to give the corresponding thiazole. Optionally, R4 as a (C1-C6) alkyl group can be introduced before reduction of the nitro group and subsequent peptide coupling with the appropriate carboxylic acid to give the expected amide. Finally, deprotection with TFA affords the corresponding N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-aryl)benzamide.

[0138] General procedure for the synthesis of N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-aryl)benzamide derivatives. A solution of N-(3-((4-(4-(di-tert-butoxycarbonylamino)pyrimidin-2-yl)thiazol-2-yl)amino)-4-aryl)benzamide derivative (0.1 mmol) in a mixture of dichloromethane-trifluoroacetic acid (3:1, 4 mL) was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was purified by flash chromatography to give the corresponding N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-aryl)benzamide.

[0139] N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide dCKi-1 (78%) as a white powder. 1 H NMR (400 MHz, MeOD) δ 8.40 (d, J = 1.7 Hz, 1H), 8.13 (d, J = 6.0 Hz, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.66 (dd, J = 8.2, 1.7 Hz, 1H), 7.60 (s, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.2 Hz, 1H), 6.44 (d, J = 6.0 Hz, 1H), 3.61 (brs, 2H), 2.53 (brs, 8H), 2.32 (s, 3H), 2.30 (s, 3H); 13 C NMR (100 MHz, MeOD) δ 168.4, 167.5, 165.5, 161.2, 155.8, 151.1, 142.9, 140.7, 138.8, 135.4, 131.9, 130.6, 128.7, 125.5, 117.0, 113.9, 112.7, 104.6, 63.3, 55.7, 53.5, 45.9, 17.6; LCMS C 27 H 30 FN8OS method (D) Rt = 3.579 min, ESI+ m / z = 515.2 (M+H).

[0140] N-(1-(4-(4-aminopyrimidin-2-yl)thiazol-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide OR0289 (66%) as a white solid. Rf=0.40 (DCM-MeOH-NH4OH, 85:13.5:1.5); 1 H NMR (400 MHz, MeOD) δ 8.08 (d, J = 6.0 Hz, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.83 (d, J = 2.0 Hz, 1H), 7.62 (dd, J = 8.2, 2.1 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.37 (s, 1H), 7.30 (d, J = 8.3 Hz, 1H), 6.41 (d, J = 6.0 Hz, 1H), 3.95 (m, 2H), 3.58 (s, 2H), 2.78-2.67 (m, 2H), 2.57 (s, 8H), 2.34 (s, 3H), 1.93 (m, 2H), 1.69 (m, 2H); 13 C NMR (100 MHz, MeOD) δ 170.78, 168.40, 165.47, 161.24, 155.30, 151.56, 146.10, 142.94, 139.56, 138.08, 135.09, 132.21, LC method (C) R t = 2.822 minutes.

[0141] N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide OR0105 (86%) as a white solid. Rf=0.18 (DCM-MeOH-NH4OH, 90:9:1). 1 H NMR (400 MHz, MeOD) δ 8.14 (d, J = 6.0 Hz, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.78 (d, J = 2.0 Hz, 1H), 7.72 (dd, J = 8.3, 2.2 Hz, 1H), 7.51 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.38 (s, 1H), 6.45 (d, J = 6.0 Hz, 1H), 4.01 (brs, 2H), 3.64 (s, 2H), 2.57 (brs, 8H), 2.34 (s, 3H), 2.26 (s, 3H), 1.86 - 1.69 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H); LC method (C) R t = 3.967 minutes.

[0142] N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)-2-((4-methylpiperazin-1-yl)methyl)pyrimidine-5-carboxamide OR0125 (81%) as a pale orange powder. Rf=0.23 (DCM-MeOH-NH4OH, 80:20:0.2); 1 H NMR (400 MHz, MeOD) δ 9.33 (s, 2H), 8.54 (d, J = 1.9 Hz, 1H), 8.14 (d, J = 6.0 Hz, 1H), 7.70 (dd, J = 8.2, 1.9 Hz, 1H), 7.63 (s, 1H), 7.21 LC method (D) R t= 3.967 minutes.

[0143] N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-4-(2-(4-methylpiperazin-1-yl)ethyl)benzamide OR0146 (49%) as orange crystals. Rf=0.55 (DCM-MeOH-NH4OH, 80:18:2). 1 H NMR (400 MHz, MeOD) δ 8.42 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 6.0 Hz, 1H), 7.88 (d, J = 8.3 Hz, 2H), 7.61 (dd, J = 8.5, 2.0 Hz, 1H), 7.59 (s, 1H), 7.32 (d, J = 8.3 Hz, 2H), 7.16 (d, J = 8.5 Hz, 1H), 6.41 (d, J = 6.0 Hz, 1H), 2.88 - 2.81 (m, 2H), 2.65 - 2.59 (m, 2H), 2.59 (s, 8H), 2.32 (s, 3H), 2.29 (s, 3H); 13 C NMR (100 MHz, MeOD) δ 168.39, 167.34, 165.46, 160.96, 155.39, 150.83, 145.51, 140.60, 138.79, 134.16, 131.85, 129.92, LC method (D) R t = 3.592 minutes.

[0144] N-(3-((4-(4-amino-5-fluoropyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide OR0239 (57%) as a white powder. 1H NMR (400 MHz, MeOD) δ 8.33 (d, J = 1.8 Hz, 1H), 8.10 (d, J = 3.6 Hz, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.64 (dd, J = 8.3, 1.8 Hz, 1H), 7.54 (s, LC method (D) R t = 3.548 minutes

[0145] N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-4-((dimethylamino)methyl)benzamide OR0155. (77%) as a white solid. Rf=0.20 (DCM-MeOH-NH4OH, 90:9:1); 1 H NMR (400 MHz, MeOD) δ 8.39 (s, 1H), 8.11 (s, 1H), 7.96 (d, J = 8.1 Hz, 2H), 7.62 (m, 1H), 7.60 (s, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 8.0 Hz, 1H), 6.43 (d, J = 6.1 Hz, 1H), 3.60 (s, 2H), 2.31 (s, 3H), 2.30 (s, 6H); 13 C NMR (100 MHz, MeOD) δ 168.32, 167.53, 165.52, 161.13, 155.60, 152.54, 142.42, 140.58, 138.80, 135.63, 131.92, 130.83, LC method (D) R t = 3.703 minutes.

[0146] N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-4-((6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)benzamide OR0156 (10%, over 2 steps) as a white solid. Rf=0.18 (DCM-MeOH-NH4OH, 80:20:2). 1 H NMR (400 MHz, MeOD) δ 8.42 (d, J = 2.0 Hz, 1H), 8.13 (d, J = 6.0 Hz, 1H), 7.96 (d, J = 8.1 Hz, 2H), 7.63 (s, 1H), 7.52 (dd, J = 8.2, 2.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 8.3 Hz, 1H), 6.46 (d, J = 6.1 Hz, 1H), 3.98 (s, 4H), 3.72 (s, 2H), 3.49 (s, 4H), 2.69 (s, 3H), 2.33 (s, 3H).

[0147] N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-5-((4-methylpiperazin-1-yl)methyl)thiophene-2-carboxamide OR0241 (83%) as a white powder. 1 H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 9.37 (brs, 1H), 8.08 (d, J = 5.8 Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.83 (d, J = 3.8 Hz, 1H), 7.47 (s, 1H), 7.45 (dd, J = 8.4, 1.8 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 3.8 Hz, 1H), 6.79 (brs, 2H), 6.31 (d, J = 5.8 Hz, 1H), 3.68 (s, 2H), 2.42 (brs, 4H), 2.33 (brs, 4H), 2.23 (s, 3H), 2.15 (s, 3H); LC method (D) Rt = 3.725 minutes.

[0148] General procedure for the synthesis of di-tert-butyl (2-(2-((3-benzamidoaryl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate derivatives. To a solution of di-tert-butyl (2-(2-((3-aminoaryl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate derivative (0.37 mmol) and an appropriate acid (0.56 mmol) in dry dimethylformamide (6 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (170 mg, 0.44 mmol) and diisopropylethylamine (330 μL, 1.85 mmol) in one portion. The resulting mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL) and washed twice successively with water (20 mL) and saturated aqueous Na2CO3 (20 mL). The organic layer was dried over Na2SO4, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography to give the corresponding di-tert-butyl (2-(2-((3-benzamidoaryl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate.

[0149] Di-tert-butyl (2-(2-((2-methyl-5-(4-(2-(4-methylpiperazin-1-yl)methyl)benzamido)phenyl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate dCKi-1-1 (38%) as a white powder. 1H NMR (300 MHz, CDCl3) 6.68 (d, J = 5.7, 1H), 8.19 (s, 1H), 7.93 (brs, 1H), 7.84 (d, J = 8.0, 2H), 7.55 (s, 1H), 7.54 (d, J = 5.6, 1H), 7.45-7.41 (m, 3H), 7.22-7.18 (m, 2H), 3.57 (s, 2H), 2.51 (brs, 8H), 2.33 (s, 3H), 2.29 (s, 3-H), 1.55 (s, 18H); 13 C NMR (75 MHz, CDCl3) δ 165.7, 165.5, 159.9, 158.6, 150.3, 149.7, 142.8, 138.9, 137.4, 133.8 , 131.6, 129.5, 127.2, 124.2, 115.3, 112.5, 110.9, 110.6, 84.4, 77.4, 62.6, 52.2, 53.0, 46.0, 28.0, 17.6; LCMS C 37 H 46 N8O5S method (D) R t = 4.908 min, ESI+ m / z = 715.3(M+H).

[0150] Di-tert-butyl (2-(2-(8-(4-((4-methylpiperazin-1-yl)methyl)benzamido)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0289-1 (45%) as a white foamy solid. Rf=0.30 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, MeOD) δ 8.74 (d, J = 5.7 Hz, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.85 (d, J = 2.0 Hz, 1H), 7.64 (dd, J = 8.3, 2.1 Hz, 1H), 7.56 (d, J = 5.7 Hz, 1H), 7.49 (d, J = 8.3 Hz, 2H), 7.46 (s, 1H), 7.35 (d, J = 8.3 Hz, 1H), 4.05 (brs, 2H), 3.67 (s, 2H), 2.95 - 2.82 (brs, 4H), 2.69 - 2.50 (brs, 4H), 2.75 (m, 2H), 2.59 (s, 3H), 1.98 (s, 2H), 1.74 (m, 2H), 1.54 (s, 18H); 13 C NMR (100 MHz, MeOD) δ 171.20, 168.46, 161.55, 160.25, 159.48, 151.57, 151.18, 146.12, 142.77, 139.61, 138.22, 135.24, 132.29, 130.45, 128.82, 121.86, 121.46, 113.68, 113.03, 85.64, 62.68, 55.31, 52.29, 52.19, 44.76, 34.89, 29.57, 28.07, 27.62; LC method (C) R t = 4.143 minutes.

[0151] Di-tert-butyl (2-(2-((2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)benzamido)phenyl)(propyl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0105-1 (55%) as a white powder, used in the next step without further purification.

[0152] Di-tert-butyl (2-(2-((2-methyl-5-(2-((4-methylpiperazin-1-yl)methyl)pyrimidine-5-carboxamido)phenyl)(propyl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0125-1 (26%) as an orange powder. Rf=0.42 (DCM-MeOH-NH4OH, 90:9:1); 1 H NMR (400 MHz, MeOD) δ 9.38 (s, 2H), 8.69 (d, J = 5.7 Hz, 1H), 8.34 (d, J = 1.3 Hz, 1H), 7.58 (dd, J = 8.3, 1.3 Hz, 1H), 7.52 (d, J = 5.7 Hz, 1H), 7.49 (s, 1H), 7.16 (d, J = 8.3 Hz, 1H), 3.91 (s, 2H), 3.09 (brs, 8H), 2.31 (s, 6H), 1.53 (s, 18H).

[0153] Di-tert-butyl (2-(2-((2-methyl-5-(4-(2-(4-methylpiperazin-1-yl)ethyl)benzamido)phenyl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0146-1 (28%) as a white foamy solid. Rf=0.36 (DCM-MeOH-NH4OH, 90:9:1); 1 H NMR (400 MHz, MeOD) δ 8.73 (d, J = 5.6 Hz, 1H), 8.36 (d, J = 1.4 Hz, 1H), 7.92 (d, J = 8.1 Hz, 2H), 7.64 (s, 1H), 7.61 (dd, J = 8.3, 1.5 Hz, 1H), 7.59 (d, J = 5.5 Hz, 1H), 7.39 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 8.3 Hz, 1H), 3.09 (brs, 4H), 2.91 (m, 2H), 2.85 (brs, 4H), , 2.80 (m, 2H), 2.72 (s, 3H), 2.30 (s, 3H), 1.53 (s, 18H); 13C NMR (100 MHz, MeOD) δ 168.40, 168.16, 161.12, 160.25, 159.55, 151.40, 150.24, 145.04, 140.44, 138.76, 134.14, 131.98, LC method (D) R t = 4.960 minutes.

[0154] Di-tert-butyl (5-fluoro-2-(2-((2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)benzamido)phenyl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0239-1 (31%) as a light brown powder. 1 H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 1.3 Hz, 1H), 8.19 (d, J = 1.8 Hz, 1H), 7.84 (d, J = 8.2 Hz, 2H), 7.78 (dd, J = 8.2, 1.3 Hz, 1H), 7.61 (s, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.2 Hz, 1H), 3.57 (s, 2H), 2.48 (brs, 8H), 2.31 (s, 3H), 2.29 (s, 3H), 1.45 (s, 18H).

[0155] Di-tert-butyl (2-(2-((2-methyl-5-(5-((4-methylpiperazin-1-yl)methyl)thiophene-2-carboxamido)phenyl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0241-1 (31%) as a yellow powder. Rf=0.53 (DCM-MeOH-NH4OH, 95:5:0.5); 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 5.7 Hz, 1H), 8.18 (d, J = 1.8 Hz, 1H), 8.07 (brs, 1H), 7.60-7.50 (m, 3H), 7.39 (brs, 1H), 7.26-7.18 (m, 2H), 6.90 (d, J = 3.6 Hz, 1H), 3.74 (s, 2H), 2.67 (brs, 8H), 2.44 (s, 3H), 2.27 (s, 3H), 1.56 (s, 18H).

[0156] Di-tert-butyl (2-(2-((5-(4-((dimethylamino)methyl)benzamido)-2-methylphenyl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0155-1. To a solution of di-tert-butyl (2-(2-((5-amino-2-methylphenyl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate dCKi-1-2 (195 mg, 0.391 mmol) in a mixture of tetrahydrofuran and dimethylformamide (4:1, 5 mL) under argon at 0 °C, N,N-diisopropylethylamine (DIPEA) (400 μL, 2.30 mmol) and a freshly prepared suspension of 4-((dimethylamino)methyl)benzoyl chloride hydrochloride (108 mg, 0.463 mmol) in tetrahydrofuran (4 mL) were added successively. After the addition, the resulting mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in saturated aqueous NaCO (20 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified by flash chromatography, gradient (DCM-MeOH-NHOH, 90:10:1) to give 4-((dimethylamino)methyl)-N-(3-((4-(4-(di-tertbutoxycarbonylamino)pyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)benzamide OR0155-1 (75 mg, 29%) as a white solid. Rf=0.10 (DCM-MeOH-NHOH, 95:5:1). 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.54 (s, 1H), 8.17 (s, 1H), 7.88 (d, J = 6.8 Hz, 2H), 7.53-7.34 (m, 5H), 7.09 (d, J = 7.6 Hz, 1H), 3.70 (s, 2H), 2.37 (s, 6H), 2.20 (s, 3H), 1.52 (s, 18H). 13 C NMR (100 MHz, CDCl3) δ 166.19, 165.81, 159.74, 158.44, 158.32, 150.21, 149.51, 138.81, 137.52, 134.84, 131.38, 130.06, LC method (D) R t = 5.229 minutes.

[0157] General procedure for the synthesis of di-tert-butyl (2-(2-((3-aminoaryl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate derivatives. To a solution of di-tert-butyl (2-(2-((3-nitroaryl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate derivatives (0.5 mmol) in a tetrahydrofuran-ethanol mixture (10:1, 22 mL) was added tin(II) chloride dihydrate (1.14 g, 5.06 mmol). The reaction mixture was stirred overnight at room temperature until the reaction was complete, as indicated by TLC or LCMS monitoring. The reaction was quenched with saturated aqueous Na2CO3 (20 mL) and stirred for an additional 15 minutes. After dilution with EtOAc (70 mL) and filtration through a short Celite pad, the aqueous layer was extracted twice with EtOAc (70 mL). The combined organic layers were dried over Na2SO4, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography to give the corresponding di-tert-butyl (2-(2-((3-aminoaryl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate.

[0158] Di-tert-butyl (2-(2-((5-amino-2-methylphenyl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate dCKi-1-2 (77%) as an orange foamy solid. Rf=0.40 (DCM-MeOH, 95:5); 1 H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 5.7 Hz, 1H), 7.51 (d, J = 5.7 Hz, 1H), 7.48 (s, 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 2.3 Hz, 1H), 6.43 (dd, J = 8.0, 2.3 Hz, 1H), 3.67 (s, 2H), 2.18 (s, 3H), 1.55 (s, 18H); 13 C NMR (75 MHz, CDCl3) δ 166.6, 158.6, 150.3, 149.9, 145.8, 139.2, 132.0, 119.3, 111.8, 111.7, 111.0, 107.1, 84.4, 77.4, 28.0, 17.1; LCMS C 24 H 30 N6O4S method (D) R t = 5.154 min, ESI+ m / z = 499.2 (M+H).

[0159] Di-tert-butyl (2-(2-(8-amino-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0289-2 (71%) as a yellow foamy solid. Rf=0.20 (DCM-MeOH, 95:5); 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 5.7 Hz, 1H), 7.47 (d, J = 5.7 Hz, 1H), 7.37 (s, 1H), 7.04 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 2.1 Hz, 1H), 6.57 (dd, J = 8.0, 2.3 Hz, 1H), 3.97 (brs, 2H), 3.45 (brs, 2H), 2.70 - 2.55 (m, 2H), 1.90 (m, 2H), 1.63 (s, 2H), 1.53 (s, 18H); 13 C NMR (100 MHz, CDCl3) δ 169.99, 160.40, 158.51, 158.39, 150.45, 150.32, 145.79, 145.53, 131.66, 130.85, 115.07, 114.64, 112.63, 110.45, 84.25, 51.01, 33.46, 28.48, 27.92, 26.77; LC method (C) R t = 4.122 minutes.

[0160] Di-tert-butyl (2-(2-((5-amino-2-methylphenyl)(propyl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0105-2 (78%) as a yellow foamy solid. Rf=0.30 (DCM-MeOH, 95:5); 1 H NMR (400 MHz, CDCl3) δ 8.72 (d, J = 5.7 Hz, 1H), 7.47 (d, J = 5.7 Hz, 1H), 7.37 (s, 1H), 7.11 (d, J = 8.2 Hz, 1H), 6.68 (dd, J = 8.1, 2.2 Hz, LC method (D)R t = 5.050 minutes.

[0161] Di-tert-butyl (2-(2-((5-amino-2-methylphenyl)amino)thiazol-4-yl)-5-fluoropyrimidin-4-yl)carbamate OR0239-2 (70%) as a yellow powder. 1 H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 7.55 (s, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 2.0, 1H), 6.45 (dd, J = 8.0, 2.0 Hz, 1H), 3.67 (brs, 2H), 2.19 (s, 3H), 1.45 (s, 18H); LC method (D) R t = 5.101 minutes.

[0162] Di-tert-butyl (2-(2-((5-nitro-2-methylphenyl)(propyl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0105-3. To a stirred solution of di-tert-butyl (2-(2-((2-methyl-5-nitrophenyl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate dCKi-1-3 (400 mg, 0.757 mmol) in a mixture of tetrahydrofuran and dimethylformamide (5:2, 14 mL) under argon at 0° C., sodium hydride (60% in mineral oil, 38 mg, 0.95 mmol) was added. After the addition, the reaction mixture was stirred at 0° C. for 30 minutes, warmed to room temperature, and stirred at this temperature for an additional 30 minutes. Propyl bromide (90 μL, 0.99 mmol) was then added at 0° C., and the resulting suspension was heated to 60° C. for 3 days. The reaction was carefully quenched with methanol (10 ml) at 0° C. and concentrated under reduced pressure. The residue was purified by flash chromatography, gradient cyclohexane-EtOAc (95:5 to 85:15) to give di-tert-butyl (2-(2-((5-nitro-2-methylphenyl)(propyl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0105-3 (142 mg, 33%) as a white solid. Rf=0.67 (PE-EtOAc, 1:1); 1H NMR (400 MHz, CDCl3) δ 8.72 (d, J = 5.7 Hz, 1H), 8.18 (dd, J = 8.4, 2.2 Hz, 1H), 8.16 (d, J = 2.2 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.52 (d, LCMS C 27 H 34 N6O6S method (B) R t = 8.987 min, ESI+ m / z = 571.3 (M+H).

[0163] General procedure for the synthesis of di-tert-butyl (2-(2-((3-nitroaryl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate derivatives. To a stirred solution of the appropriate di-tert-butyl (2-(2-bromoacetyl)-pyrimidin-4-yl)carbamate (1.3 mmol) and 1-(3-nitroaryl)thiourea (1.22 mmol) in ethanol (40 mL) was added potassium carbonate (258 mg, 1.87 mmol). The resulting mixture was stirred at the temperature and for the time indicated below. The solvent was evaporated under reduced pressure. The residue was purified by flash chromatography to give the corresponding di-tert-butyl (2-(2-((3-nitroaryl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate.

[0164] Di-tert-butyl (2-(2-((2-methyl-5-nitrophenyl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate dCKi-1-3 (96%) as a dark orange foamy solid. Rf=0.10 (PE-EtOAc, 1:1); 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 5.7 Hz, 1H), 8.47 (d, J = 2.2 Hz, 1H), 7.90 (dd, J = 8.3, 2.2 Hz, 1H), 7.60 (s, 1H), 7.55 (d, J = 5.7 Hz, 1H), 7.38 (d, J = 8.3 Hz, 1H), 2.40 (s, 3H), 1.56 (s, 18H); LCMS C 24 H 28 N6O6S,Method (B) R t = 8.197 min, ESI+ m / z = 529.2 (M+H).

[0165] Di-tert-butyl (2-(2-(8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0289-3 (50%) as a yellow foamy solid. Rf=0.20 (DCM-MeOH, 98:2); 1 H NMR (400 MHz, CDCl3) δ 8.73 (d, J = 5.8 Hz, 1H), 8.32 (d, J = 2.2 Hz, 1H), 8.10 (dd, J = 8.4, 2.2 Hz, 1H), 7.54 (d, J = 5.8 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.46 (s, 1H), 4.06 (brs, 2H), 2.91 - 2.82 (m, 2H), 2.01-1.88 (m, 2H), 1.75 (brs, 2H), 1.54 (s, 18H). 13 C NMR (100 MHz, CDCl3) δ 168.86, 159.95, 158.57, 158.35, 150.25, 148.70, 147.50, 145.45, 131.81, 123.56, 123.51, 122.87, 113.21, 110.52, 84.37, 51.08, 34.24, 28.24, 27.92, 25.42; LCMS C 27 H 32 N6O6S,Method (B) R t= 8.694 min, ESI+ m / z = 569.3 (M+H).

[0166] Di-tert-butyl (5-fluoro-2-(2-((2-methyl-5-nitrophenyl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0239-3 (83%) as a deep orange solid. 1 H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.52 (d, J = 2.2 Hz, 1H), 7.92 (dd, J = 8.3, 2.2 Hz, 1H), 7.71 (s, 1H), 7.40 (d, J = 8.3 Hz, 1H), 2.42 (s, 3H), 1.46 (s, 18H); LCMS C 24 H 27 FN6O6S,Method (A) R t = 7.871 min, ESI- m / z = 545.2 (MH).

[0167] General procedure for the synthesis of 1-(3-nitroaryl)thiourea derivatives. A suspension of the appropriate N-((3-nitroaryl)carbamothioyl)acetamide (2 mmol) and potassium carbonate (1.53 g, 11.1 mmol) in methanol (10 mL) was stirred at room temperature until complete consumption of the starting material was monitored by TLC or LCMS. The solvent was evaporated under reduced pressure, and the residue was poured onto water (30 mL) and then extracted with DCM (3 × 50 mL). The combined organic layers were dried over NaSO, and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography to give the corresponding 1-(3-nitroaryl)thiourea.

[0168] 1-(2-methyl-5-nitrophenyl)thiourea dCKi-1-4 (90%) as a pale yellow solid. Rf=0.20 (PE-EtOAc, 1:1); 1H NMR (300 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.27 (d, J = 2.4 Hz, 1H), 7.98 (dd, J = 8.4, 2.4 Hz, 1H), 7.70 (s, 2H), 7.51 (d, J = 8.5 Hz, 1H), 2.31 (s, 3H); LCMS C8H9N3O2S method (D) R t = 4.675 points, ESI+ m / z = 212.1 (M+H).

[0169] N-8-ニトロ-2,3,4,5-テトラヒドロ-1H-ベンゾ[b]アゼピン-1-カルボチオアミドOR0289-4 (79%), white solid として. Rf=0.31(DCM-MeOH, 98:2); 1 H NMR (400 MHz, CDCl3) δ 8.20-8.12 (m, 2H), 7.51 (d, J = 7.9 Hz, 1H), 5.62 (brs, 2H), 5.31 (d, J = 12.8 Hz, 1H), 2.99 (t, J = 12.8 Hz, 1H), 2.86 (m, 2H), 2.33 (m, 1H), 2.09 (d, J = 14.0 Hz, 1H), 1.83 (d, J = 13.9 Hz, 1H), 1.41 (m, 1H); LCMS C 11 H 13 N3O2S method (B) R t = 5.782 points, ESI+ m / z = 252.1 (M+H).

[0170] General procedure for the synthesis of N-((3-nitroaryl)carbamothioyl)acetamide derivatives. Under argon, to a suspension of potassium thiocyanate (982 mg, 10 mmol) in acetone (30 mL) was added dropwise acetyl chloride (0.60 mL, 7.95 mmol). The resulting solution was refluxed for 3 h. After cooling to room temperature, a solution of the appropriate 3-nitroaniline (7.68 mmol) in acetone (20 mL) was added dropwise. The mixture was stirred at room temperature overnight, after which complete consumption of the starting material was monitored by TLC or LCMS. The solvent was evaporated under reduced pressure, and the residue was poured onto water (100 mL) and stirred for 1 h. The resulting precipitate was collected by filtration to give the corresponding N-((3-nitroaryl)carbamothioyl)acetamide.

[0171] N-((2-methyl-5-nitrophenyl)carbamothioyl)acetamide dCKi-1-5 (99%) as a dark orange powder. Rf = (PE-EtOAc, 85:15); 1 H NMR (300 MHz, DMSO-d6) δ 12.37 (s, 1H), 11.67 (s, 1H), 8.67 (d, J = 2.4 Hz, 1H), 8.06 (dd, J = 8.4, 2.4 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 2.33 (s, 3H), 2.18 (s, 3H); LCMS C 10 H 11 N3O3S method (B) R t = 6.036 min, ESI+ m / z = 254.1 (M+H).

[0172] N-(8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carbonothioyl)acetamide OR0289-5 (93%) as a light brown solid. LCMS C 13 H 15 N3O3S, method (B)R t =6.061 min, ESI+m / z=294.1(M+H).

[0173] 8-Nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine OR0289-6 A mixture of the solid fraction, 2,3,4,5-tetrahydro-1H-benzo[b]azepine (2.94 g, 20 mmol), and potassium nitrate (2.02 g, 20 mmol) was added to concentrated sulfuric acid (30 mL) over 30 min at −5 °C under stirring. After the addition, the reaction mixture was poured onto ice (100 g), and then Na2CO3 was added until pH = 8–9 and extracted with DCM (3 × 20 mL). The combined organic layers were dried over Na2SO4, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography with DCM-PE (8:2) to give 8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine OR0289-6 (2.70 g, 71%) as an orange oil, which crystallized from a mixture of MeOH-Et2O-PE as orange plates. Rf = 0.35 (DCM-PE, 8:2); 1 H NMR (400 MHz, CDCl3) δ 7.67 (dd, J = 8.2, 2.3 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 3.15-3.08 (m, 2H), 2.91-2.82 (m, 2H), 1.89-1.83 (m, 2H), 1.74-1.62 (m, 2H); LCMS C 10 H 12 N2O2 method (B) R t = 6.522 min, ESI+ m / z = 193.1 (M+H).

[0174] General procedure for the synthesis of di-tert-butyl (2-(2-bromoacetyl)-pyrimidin-4-yl)carbamate derivatives. To a stirred solution of the appropriate di-tert-butyl (2-(1-ethoxyvinyl)pyrimidin-4-yl)carbamate (4 mmol) in a tetrahydrofuran-water mixture (3:1, 8 mL), N-bromosuccinimide (844 mg, 4.74 mmol) was added in one portion. The resulting solution was stirred at room temperature for 3 h until the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure without heating (T≦30° C.). The crude product was crystallized from EtO to give the corresponding di-tert-butyl (2-(2-bromoacetyl)-pyrimidin-4-yl)carbamate.

[0175] Di-tert-butyl (2-(2-bromoacetyl)-pyrimidin-4-yl)carbamate dCKi-1-6 (95%) as white crystals. Rf=0.35 (PE-EtOAc, 8:2); 1 H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 5.8 Hz, 1H), 7.93 (d, J = 5.8 Hz, 1H), 4.68 (s, 2H), 1.57 (s, 18H); LCMS C 16 H 22 BrN3O5 method (B) R t = 7.009 min, ESI+ m / z = 418.2 (M+H).

[0176] Di-tert-butyl (2-(2-bromoacetyl)-5-fluoropyrimidin-4-yl)carbamate OR0239-4 (quantitative) as white crystals was used in the next step without further purification. LCMS C 16 H 21 BrFN3O5, method (A)R t =7.256 min, ESI+m / z=234.1(M-(Boc)2).

[0177] General procedure for the synthesis of di-tert-butyl (2-(1-ethoxyvinyl)pyrimidin-4-yl)carbamate derivatives. Under argon, to a solution of the appropriate di-tert-butyl (2-chloropyrimidin-4-yl)carbamate (5.0 mmol) in dry 1,4-dioxane or toluene (50 mL) were added tributyl(1-ethoxyvinyl)tin (2.52 g, 7.0 mmol) and cesium fluoride (1.51 g, 10.0 mmol) successively. The resulting mixture was thoroughly degassed several times under an argon blanket before the addition of bis(triphenylphosphine)palladium dichloride (351 mg, 0.5 mmol, 10 mol%). The resulting mixture was warmed until the starting material was completely consumed. After cooling to room temperature, the resulting mixture was filtered through a short Celite pad and rinsed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography to give the corresponding di-tert-butyl (2-(1-ethoxyvinyl)pyrimidin-4-yl)carbamate.

[0178] Di-tert-butyl (2-(1-ethoxyvinyl)pyrimidin-4-yl)carbamate dCKi-1-7. To a solution of di-tert-butyl (2-chloropyrimidin-4-yl)carbamate dCKi-1-8 (25.5 g, 77.4 mmol) in dry 1,4-dioxane (450 mL) under argon, tributyl(1-ethoxyvinyl)tin (38.4 g, 106.2 mmol) and cesium fluoride (23.3 g, 153.0 mmol) were added sequentially. The resulting mixture was thoroughly degassed several times under an argon backfill before the addition of bis(triphenylphosphine)palladium dichloride (5.5 g, 7.75 mmol, 10 mol%). The resulting mixture was stirred at 90 °C overnight, then cooled to room temperature before being filtered through a Celite pad and washed with EtOAc (800 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography, PE-EtOAc (8:2) to give di-tert-butyl (2-(1-ethoxyvinyl)pyrimidin-4-yl)carbamate dCKi-1-7 (20.7 g, 73%) as yellow crystals, Rf=0.35 (PE-EtOAc, 8:2); 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 5.7 Hz, 1H), 7.56 (d, J = 5.7 Hz, 1H), 5.58 (d, J = 1.9 Hz, 1H), 4.57 (d, J = 1.9 Hz, 1H), 3.99 (q, J = 7.0 Hz, 2H), 1.55 (s, 18H), 1.46 (t, J = 7.0 Hz, 3H); LCMS C 18 H 27 N3O5 method (A) R t = 7.608 min, ESI+ m / z = 366.3 (M+H).

[0179] Di-tert-butyl (2-(1-ethoxyvinyl)-5-fluoropyrimidin-4-yl)carbamate OR0239-5. A stirred solution of di-tert-butyl (2-chloro-5-fluoropyrimidin-4-yl)carbamate OR0239-6 (400 mg, 1.15 mmol), tributyl(1-ethoxyvinyl)tin (550 μL, 1.61 mmol), copper(I) bromide (25 mg, 0.17 mmol), and cesium fluoride (350 mg, 2.3 mmol) in dry toluene (10 mL) was degassed under an argon blanket for 15 min. PdCl(PPh) (41 mg, 0.06 mmol) and triphenylphosphine (45 mg, 0.17 mmol) were added sequentially. Argon was bubbled through for an additional 5 minutes, and the mixture was refluxed for 4 hours, after which complete conversion was monitored by TLC. The resulting mixture was cooled to room temperature, filtered through a Celite pad, and rinsed with DCM. The crude product was purified by flash chromatography, DCM-EtOAc, to give di-tert-butyl (2-(1-ethoxyvinyl)-5-fluoropyrimidin-4-yl)carbamate OR0239-5 (401 mg, 91%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 1.4 Hz, 1H), 5.60 (d, J = 2.2 Hz, 1H), 4.62 (d, J = 2.2 Hz, 1H), 4.02 (q, J = 7.0 Hz, 2H), 1.48 (t, J = 7.0 Hz, 3H), 1.44 (s, 18H); LCMS C 18 H 26 FN3O5 method (A) R t = 7.568 min, ESI+ m / z = 384.2 (M+H).

[0180] General procedure for the synthesis of di-tert-butyl (2-chloropyrimidin-4-yl)carbamate derivatives. To a stirred solution of the appropriate 2-chloro-4-aminopyrimidine (1.95 g, 15 mmol) in tetrahydrofuran (50 mL) was added di-tert-butyl dicarbonate (8.0 g, 37 mmol) and 4-dimethylaminopyridine (124 mg, 1 mmol). The resulting solution was stirred at room temperature overnight upon completion of the reaction. The solvent was evaporated under reduced pressure, and the residue was diluted with DCM (50 mL) and washed with HO (2 × 10 mL). The organic layer was dried over NaSO and concentrated under reduced pressure to give the corresponding di-tert-butyl (2-chloropyrimidin-4-yl)carbamate.

[0181] Di-tert-butyl (2-chloropyrimidin-4-yl)carbamate dCKi-1-8 (quantitative) as a white solid. Rf=0.70 (PE-EtOAc, 85:15). 1 H NMR (300 MHz, CDCl3) δ 8.46 (d, J = 5.7 Hz, 1H), 7.71 (d, J = 5.7 Hz, 1H), 1.56 (s, 18H); LCMS C 14 H 20 ClN3O4 method (B) R t = 7.407 min, ESI+ m / z = 330.2 (M+H).

[0182] Di-tert-butyl (2-chloro-5-fluoropyrimidin-4-yl)carbamate OR0239-6 (28%) as a white powder. 1 H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 1.46 (s, 18H); LCMS C 14 H 19 ClFN3O4 method (A) R t = 7.759 min, ESI+ m / z = 192.1 (M-(Boc)2+HCO2H).

[0183] [ka]

[0184] Reagents and conditions: i) Boc2O, DMAP; ii) Tributyl(1-ethoxyvinyl)tin, Pd(PPh3)2Cl2, CsF, CuBr; iii) NBS; iv) (PinB)2, PdCl2(dppf), KOAc ;v) ArB(OH)2, PdCl2(dppf), Na2CO3; vi) H2, Pd / C, THF-EtOH; vii) optionally RCHO, NaBH(OAc)3, AcOH; viii) KSCN, AcCl or 1N HCl aq or PhCONCS; ix) K2CO3, MeOH; x) K2CO3, EtOH; xi) TFA.

[0185] N-([1,1'-biaryl]-3-yl)-4-(4-aminopyrimidin-2-yl)thiazol-2-amine derivatives were prepared in eight steps via a convergent synthesis from commercially available 4-amino-2-chloropyrimidine and the appropriate bromo-3-nitrobenzene (Scheme 2). The 4-amino-2-chloropyrimidine was protected using BocO to give the corresponding bis-carbamate. Stille cross-coupling with tributyl(1-ethoxyvinyl)tin afforded the enol ether, which was then converted to the corresponding α-bromoketone using N-bromosuccinimide. Starting from the appropriate bromo-3-nitrobenzene, Suzuki cross-coupling with the corresponding aryl boronate allowed the introduction of key biaryl scaffolds. Optional (C1-C6) alkylation followed by hydrogenation of the nitro group and subsequent condensation with potassium thiocyanate afforded the corresponding thiourea. As previously described, the α-bromoketone was used with thiourea in the Hantzsch thiazole synthesis to give the corresponding thiazole. Finally, deprotection with TFA afforded the expected N-([1,1'-biaryl]-3-yl)-4-(4-aminopyrimidin-2-yl)thiazol-2-amine.

[0186] General procedure for the synthesis of N-([1,1'-biaryl]-3-yl)-4-(4-aminopyrimidin-2-yl)thiazol-2-amine. As previously described for N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-aryl)benzamide derivatives.

[0187] 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-3-yl)thiazol-2-amine OR0274 (57%) as a white powder. 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 5.7 Hz, 1H), 7.76 (s, 1H), 7.59 (s, 1H), 7.55 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.32-7.27 (m, 2H), 6.34 (d, J = 5.7 Hz, 1H), 4.98 (brs, 2H), 3.55 (s, 2H), 2.50 (brs, 8H), 2.34 (s, 3H), 2.30 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 166.65, 163.11, 160.54, 156.49, 150.57, 140.32, 139.31, 139.17, 137.56, 131.73, 129.81, 128.70, 126.88, 123.25, 118.96, 110.94, 103.41, 62.75, 55.20, 53.11, 46.07, 17.69. LC method (D) R t = 3.558 minutes.

[0188] 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)thiazol-2-amine OR0325 (45%) as a white powder. 1 H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 5.7 Hz, 1H), 7.74 (s, 1H), 7.58 (s, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.35 (brs, 1H), 7.29-7.27 (m, 2.33 (s, 3H), 2.32 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 166.66, 163.10, 160.53, 156.48, 150.57, 140.34, 139.73, 139.16, 138.35, 131.71, 129.32, 128.62, LC method (D) R t = 3.602 minutes.

[0189] 3'-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4'-methyl-[1,1'-biphenyl]-4-ol OR0320 (58%), as a white powder. 1 H NMR (400 MHz, MeOD) δ 8.12 (d, J = 6.0 Hz, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.49 (s, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.32 (dd, J = 8.1, 1.6 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H). 6.84 (d, J = 8.6 Hz, 2H), 6.43 (d, J = 6.0 Hz, 1H), 2.34 (s, 3H). 13 C NMR (100 MHz, MeOD) δ 169.65, 165.60, 160.77, 158.24, 154.87, 150.72, 141.44, 140.88, 133.12, 132.59, 130.83, 128.88, 124.35, 122.07, 116.64, 112.10, 104.58, 17.61; LC method (D) R t = 4.369 minutes.

[0190] 3'-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4'-methyl-[1,1'-biphenyl]-4-ol OR0321 (53%) as a white powder. 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.70 (s, 1H), 7.57 (s, 1H), 7.28-7.26 (m, 2H), 7.12-6.96 (m, 3H), 6.33 (d, J = 5.5 Hz, 1H), 5.03 (brs, 2H), 3.94 (s, 3H), 2.32 (s, 3H); LC method (D) R t = 4.389 minutes.

[0191] 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-(3-(4-methylpiperazin-1-yl)propyl)-[1,1'-biphenyl]-3-yl)thiazol-2-amine OR0331 (46%) as a pale yellow powder. 1 H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 5.7 Hz, 1H), 7.74 (brs, 1H), 7.56 (s, 1H), 7.51-7.49 (m, 3H), 7.31-7.24 (m, 4H), 6.31 (d, J = 5.7 Hz, 1H), 5.05 (brs, 2H), 2.66 (t, J= 7.8 Hz, 2H), 2.47 (brs, 8H), 2.39 (t, J = 7.8 Hz, 2H), 2.31 (s, 3H), 2.28 (s, 3H), 1.81 (quintet, J = 7.8Hz, 2H); 13 C NMR (100 MHz, CDCl3) δ 166.67, 163.10, 160.55, 156.51, 150.56, 141.65, 140.45, 139.12, 138.04, 131.71, 129.02, 128.51, 126.97, 123.20, 118.89, 110.97, 103.40, 58.08, 55.26, 53.29, 46.16, 33.47, 28.71, 17.68; 28 H 33 N7S method (B) R t = 3.881 min, ESI+ m / z = 500.1 (M+H).

[0192] 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-(3-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)-N-propylthiazol-2-amine OR0345 (42%) as a colorless solid; 1 H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 5.7 Hz, 1H), 7.53-7.46 (m, 4H), 7.39-7.38 (m, 2H), 7.28-7.25 (m, 2H), 6.25 (d, J = 5.7 Hz, 1H), 5.3 (brs, 2H), 4.01 (brs, 2H), 2.86-2.82 (m, 2H), 2.87-2.51 (m, 2H), 2.52 (brs, 8H), 2.31 (s, 3H), 2.26 (s, 3H), 1.66 (sextet, J = 7.3 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 171.27, 163.14, 160.88, 156.41, 151.19, 143.27, 140.74, 139.81, 137.84, 136.17, 132.49, 129.33, LCMS C 30 H 37 N7S method (B) R t = 4.152 min, ESI+ m / z = 528.3 (M+H).

[0193] 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-(3-(4-methylpiperazin-1-yl)propyl)-[1,1'-biphenyl]-3-yl)-N-propylthiazol-2-amine OR0598 (70%) as a pale yellow solid. Rf=0.40 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 5.8 Hz, 1H), 7.53 (dd, J = 7.9, 1.7 Hz, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 1.7 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.37 (s, 1H), 7.24 (d, J = 8.1 Hz, 2H), 6.29 (d, J = 5.8 Hz, 1H), 5.10 (s, 2H), 4.02 (brs, 2H), 2.72-2.65 (m, 2H), 3.11-2.55 (m, 8H), 2.54-2.45 (m, 2H), 2.43 (s, 3H), 2.27 (s, 3H), 1.89 (quintet, J = 7.6 Hz, 2H), 1.67 (sextet, J = 7.5 Hz, 2H), 0.93 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 171.41, 163.09, 160.94, 156.53, 151.17, 143.29, 141.14, 140.78, 137.78, 136.24, 132.54, 129.04, LCMS C 31 H 39 N7S method (B) R t = 4.253 min, ESI+ m / z = 542.3 (M+H).

[0194] 2-(2-(8-(4-(2-(4-methylpiperazin-1-yl)ethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)thiazol-4-yl)pyrimidin-4-amine OR0402 (87%) as a pale yellow solid. Rf=0.18 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, MeOD) δ 8.12 (d, J = 6.0 Hz, 1H), 7.60 (d, J = 1.8 Hz, 1H), 7.56-7.47 (m, 3H), 7.38 (d, J = 7.9 Hz, 1H), 7.35 (s, 1H), 7.27 (d, J = 8.2 Hz, 2H), 6.43 (d, J = 6.0 Hz, 1H), 4.03 (brs, 2H), 2.85-2.79 (m, 2H), 2.78-2.72 (m, 2H), 2.66-2.58 (m, 2H), 2.55 (brs, 8H), 2.30 (s, 3H), 1.95-1.93 (m, 2H), 1.75-7.73 (m, 2H). 13 C NMR (100 MHz, MeOD) δ 170.97, 165.49, 161.54, 155.76, 151.89, 146.59, 142.09, 141.04, 140.70, 139.12, 132.64, 130.35, LCMS C 30 H 35 N7S method (B) R t = 4.064 min, ESI+ m / z = 526.3 (M+H).

[0195] 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethoxy)-[1,1'-biphenyl]-3-yl)-N-propylthiazol-2-amine OR0596 (63%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 5.8 Hz, 1H), 7.50 (d, J = 8.8 Hz, 2H), 7.49 (dd, J = 7.7, 1.8 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.38 (s, 1H), 7.37 (d, J = 7.7 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H), 6.27 (d, J = 5.8 Hz, 1H), 5.12 (s, 2H), 4.14 (t, J = 5.8 Hz, 2H), 4.02 (brs, 2H), 2.83 (t, J = 5.8 Hz, 2H), 2.63 (brs, 4H), 2.48 (brs, 4H), 2.29 (s, 3H), 2.26 (s, 3H), 1.67 (sextet, J = 7.4 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 171.39, 163.09, 160.98, 158.62, 156.58, 151.19, 143.28, 140.59, 135.71, 132.73, 132.49, 128.02, LCMS C 30 H 37 N7S method (B) R t = 4.304 min, ESI+ m / z = 544.2 (M+H).

[0196] 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy)-[1,1'-biphenyl]-3-yl)-N-propylthiazol-2-amine OR0597 (49%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 5.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.48 (dd, J = 8.0, 1.9 Hz, 1H), 7.42 (d, J = 1.9 Hz, 1H), 7.38 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 6.29 (d, J = 5.8 Hz, 1H), 5.04 (s, 2H), 4.72 (s, 2H), 4.03 (brs, 2H), 3.63 (m, 4H), 2.40 (m, 4H), 2.29 (s, 3H), 2.27 (s, 3H), 1.67 (sextet, J = 7.4 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 171.41, 166.40, 163.07, 161.00, 157.69, 156.63, 151.19, 143.30, 140.40, 135.97, 133.65, 132.55, 128.22, 127.81, 126.83, 115.16, 111.31, 103.16, 67.85, 55.27, 54.74, 53.51, 46.15, 45.39, 42.18, 21.33, 17.45, 11.45; LCMS C 30 H 35 N7O2S method (B) R t = 4.296 min, ESI+ m / z = 558.2 (M+H).

[0197] 4-(4-aminopyrimidin-2-yl)-N-(2-methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethyl)pyridin-3-yl)phenyl)-N-propylthiazol-2-amine OR0599 (10%) as a yellow solid. Rf=0.40 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.30 (d, J = 5.3 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.45 (s, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.39 (s, 1H), 7.24 (d, J = 7.9 Hz, 1H), 6.29 (d, J = 5.3 Hz, 1H), 5.07 (s, 2H), 4.04 (brs, 2H), 3.03 (m, 2H), 2.80 (m, 2H), 2.60 (brs, 4H), 2.48 (brs, 4H), 2.29 (s, 6H), 1.66 (sextet, J = 7.2 Hz, 2H), 0.94 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 171.20, 163.08, 160.97, 159.62, 156.65, 151.28, 147.57, 143.60, 137.68, 137.31, 134.70, 133.15, LCMS C 29 H 36 N8S method (B) R t = 3.950 min, ESI+ m / z = 529.4 (M+H).

[0198] General procedure for the synthesis of di-tert-butyl (2-(2-([1,1'-biaryl]-3-ylamino)thiazol-4-yl)pyrimidin-4-yl)carbamate derivatives. As previously described for di-tert-butyl (2-(2-((3-nitroaryl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate derivatives.

[0199] Di-tert-butyl (2-(2-((4-methyl-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0274-1 (37%) as a light brown powder. 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 5.7 Hz, 1H), 7.75 (s, 1H), 7.57-7.50 (m, 4H), 7.39 (d, J = 8.1 Hz, 2H), 7.31 (s, 2H), 3.55 (s, 2H), 2.50 (brs, 8H), 2.34 (s, 3H), 2.30 (s, 3H), 1.56 (s, 18H).

[0200] Di-tert-butyl (2-(2-((4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0325-1 (46%) as a light brown powder. 1 H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 5.7 Hz, 1H), 7.73 (s, 1H), 7.53-7.51 (m, 4H), 7.33-7.26 (m, 4H), 2.85 (dd, J = 9.9, 6.4 Hz, 2H), 2.65 (dd, J = 9.9, 6.4 Hz, 1H), 2.53 (brs, 8H), 2.34 (s, 3H), 2.32 (s, 3H), 1.56 (s, 18H); LC method (C) R t = 3.933 minutes.

[0201] Di-tert-butyl (2-(2-((4'-hydroxy-4-methyl-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0320-1 (48%) as a light brown powder. 1H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 5.7 Hz, 1H), 7.66 (s, 1H), 7.53 (d, J = 5.7 Hz, 1H), 7.50 (s, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.27-7.25 (m, 1H), 6.92 (d, J = 8.6 Hz, 2H), 2.30 (s, 3H), 1.56 (s, 18H); LC method (A) R t = 8.406 minutes.

[0202] Di-tert-butyl (2-(2-((4'-hydroxy-3'-methoxy-4-methyl-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0321-1 (52%) as a light brown powder. 1 H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 5.6 Hz, 1H), 7.70 (s, 1H), 7.54 (d, J = 5.6 Hz, 1H), 7.51 (s, 1H), 7.28-7.26 (m 2H), 7.13-7.05 (m, LCMS C 31 H 35 N5O6S method (A) R t = 8.452 min, ESI+ m / z = 606.3 (M+H).

[0203] Di-tert-butyl (2-(2-((4-methyl-4'-(2-(4-methylpiperazin-1-yl)propyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0331-1 (58%) as a yellow powder. LCMS C 38 H 49 N7O4S, method (B)R t =5.470 min, ESI+m / z=700.4(M+H).

[0204] Di-tert-butyl (2-(2-((4-methyl-4'-(3-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0345-1 (47%) as a yellow powder. Rf=0.42 (DCM-MeOH-NH4OH, 90:9:1). 1 H NMR (400 MHz, CDCl3) δ 8.73 (d, J = 5.7 Hz, 1H), 7.55-7.46 (m, 4H), 7.41-7.39 (m, 2H), 7.31-7.24 (m, 3H), 5.3 (brs, 2H), 3.99 (brs, LCMS C 40 H 53 N7O4S method (B) R t = 5.040 min, ESI+ m / z = 728.4 (M+H).

[0205] Di-tert-butyl (2-(2-((4-methyl-4'-(3-(4-methylpiperazin-1-yl)propyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0598-1 (85%) as a light brown powder. Rf=0.42 (DCM-MeOH-NH4OH, 90:9:1). 1H NMR (400 MHz, CDCl3) δ 8.73 (d, J = 5.7 Hz, 1H), 7.54 (dd, J = 7.9, 1.7 Hz, 1H), 7.50 (d, J = 8.6 Hz, 2H), 7.46-7.48 (m, 2H), 7.40 (d, J = 8.0 Hz, 1H), 7.37 (s, 1H), 7.24 (d, J = 8.2 Hz, 2H), 4.03 (brs, 2H), 2.94 (s, 8H), 2.96-2.87 (m, 2H), 2.70 (t, J = 7.4 Hz, 2H), 2.57 (s, 3H), 2.28 (s, 3H), 1.98-1.94 (m, 2H), 1.68 (sextet, J = 7.4 Hz, 2H), 1.54 (s, 18H), 0.94 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 171.50, 160.50, 158.62, 158.55, 150.61, 150.37, 143.29, 140.75, 137.98, 136.32, 132.62, 129.04, 128.10, 127.23, 127.10, 112.49, 110.62, 84.24, 57.02, 55.86, 53.56, 53.36, 51.06, 32.95, 28.00, 27.96, 21.32, 17.46, 11.48; LCMS C 41 H 55 N7O4S method (B) R t = 5.956 min, ESI+ m / z = 742.4 (M+H).

[0206] Di-tert-butyl (2-(2-(8-(4-(2-(4-methylpiperazin-1-yl)ethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0402-1 (60%) as a light brown powder. Rf=0.42 (DCM-MeOH-NH4OH, 90:9:1); LCMS C 40 H 51 N7O4S, method (B)R t=5.603 min, ESI+m / z=726.3(M+H).

[0207] Di-tert-butyl (2-(2-((4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethoxy)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0596-1 (94%) as a colorless oil. Rf=0.42 (DCM-MeOH-NH4OH, 90:9:1); LCMS C 40 H 53 N7O5S, method (B)R t =5.949 min, ESI+m / z=744.4(M+H).

[0208] Di-tert-butyl (2-(2-((4-methyl-4'-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0597-1 (82%) as a light brown solid. Rf=0.42 (DCM-MeOH-NH4OH, 90:9:1); LCMS C 40 H 53 N7O5S, method (B)R t =5.889 min, ESI+m / z=758.2(M+H).

[0209] Di-tert-butyl (2-(2-((2-methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0599-1 (67%) as a light brown powder. Rf=0.42 (DCM-MeOH-NH4OH, 90:9:1); LCMS C 39 H 52 N8O4S, method (B)R t =5.489 min, ESI+m / z=729.6(M+H).

[0210] General procedure for the synthesis of 1-([1,1'-biaryl]-3-yl)thiourea derivatives. Method (A): As previously described for 1-(3-nitroaryl)thiourea derivatives. Method (B): To a solution of the appropriate [1,1'-biaryl]-3-amine (0.70 mmol) in 1N aqueous hydrochloric acid (7 mL), potassium thiocyanate (312 mg, 3.2 mmol) was added. The resulting solution was continuously stirred at 90 °C for 48 h, cooled to room temperature, and then saturated aqueous NaHCO3 was added until pH = 8 and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over Na2SO4, and the solvent was evaporated under reduced pressure. The residue was purified by chromatography to give the corresponding 1-([1,1'-biaryl]-3-yl)thiourea.

[0211] 1-(4-methyl-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-3-yl)thiourea OR0274-2 (Method A, 39%) as a white powder. 1 H NMR (400 MHz, MeOD) δ 7.59 (d, J = 8.3 Hz, 2H), 7.52 (dd, J = 7.9, 1.9 Hz, 1H), 7.49 (d, J = 1.9 Hz, 1H), 7.40 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 7.9 Hz, 1H), 4.58 (s, 2H), 2.54 (brs, 8H), 2.31 (s, 3H), 2.30 (s, 3H).

[0212] 1-(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)thiourea OR0325-2 (Method A, 77%) as a white powder. 1 H NMR (400 MHz, MeOD) δ 7.59-7.46 (m, 4H), 7.40-7.35 (m, 1H), 7.30-7.27 (m, 2H), 2.88-2.82 (m, 2H), 2.66-2.62 (m, 2H), 2.56 (brs, 8H), 2.31 (s, 6H); LC method (D) R t = 3.256 minutes.

[0213] 1-(4'-hydroxy-4-methyl-[1,1'-biphenyl]-3-yl)thiourea OR0320-2 (Method A, 86%) as a white powder. 1 LCMS C 14 H 14 N2OS method (A) R t = 5.366 min, ESI- m / z = 257.4 (MH).

[0214] 1-(4'-hydroxy-3'-methoxy-4-methyl-[1,1'-biphenyl]-3-yl)thiourea OR0321-2 (Method A, 74%) as a white powder. 1 H NMR (400 MHz, MeOD) δ 7.47 (dd, J = 7.9, 1.9 Hz, 1H), 7.42 (d, J = 1.9 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 7.06 (dd, J LCMS C 15 H 16 N2O2S method (A) R t = 5.448 min, ESI+ m / z = 289.1 (M+H).

[0215] 1-(4-methyl-4'-(2-(4-methylpiperazin-1-yl)propyl)-[1,1'-biphenyl]-3-yl)thiourea OR0331-2 (Method B, 73%) as a pale yellow solid. LCMS C 22 H 30 N4S, Method (B)R t =7.139 min, ESI+m / z=383.3(M+H).

[0216] 1-(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)-1-propylthiourea OR0345-2 (Method B, quantitative), as a yellow powder. 1 H NMR (400 MHz, CDCl3) δ 7.53 (dd, J = 7.9, 1.9 Hz, 1H), 7.46 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.29 (d, J = 8.2 Hz, 2H), 5.47 (brs, 2H), 4.46-4.42 (m, 1H), 3.86-3.79 (m, 1H), 2.87-2.82 (m, 2H), 2.65-2.59 (m, 2H), 2.51 (brs, 8H), 2.33 (s, 3H), 2.31 (s, 3H), 1.87-1.78 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H); LCMS C 24 H 34 N4S method (C) R t = 3.455 min, ESI+ m / z = 411.3 (M+H).

[0217] 1-(4-methyl-4'-(3-(4-methylpiperazin-1-yl)propyl)-[1,1'-biphenyl]-3-yl)-1-propylthiourea OR0598-2 (Method A, 90%) as a pale yellow solid. Rf=0.36 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, CDCl3) δ 7.53 (dd, J = 7.9, 1.8 Hz, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 1.8 Hz, 1H), 7.26 (d, J = 8.1 Hz, 2H), 5.51 (brs, 2H), 4.51-4.41 (m, 1H), 3.72-3.61 (m, 1H), 2.72-2.64 (m, 2H), 2.56 (brs, 8H), 2.46-2.40 (m, 2H), 2.33 (s, 3H), 2.26 (s, 3H), 1.87 (quintet, J = 7.7 Hz, 2H), 1.86-1.62 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H); LCMS C 25 H 36 N4S method (B) R t = 4.417 min, ESI+ m / z = 425.3 (M+H).

[0218] 8-(4-(2-(4-methylpiperazin-1-yl)ethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carbothioamide OR0402-2 (Method A, 92%) was used in the next step without workup or purification. LCMS C 24 H 32 N4S, Method (B)R t =3.405 min, ESI+m / z=409.3(M+H).

[0219] 1-(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethoxy)-[1,1'-biphenyl]-3-yl)-1-propylthiourea OR0596-2 (Method A, 61%) as a white solid. Rf=0.36 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, CDCl3) δ 7.50 (dd, J = 8.0, 1.8 Hz, 1H), 7.46 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 1.8 Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H), 5.49 (brs, 2H), 4.49-4.41 (m, 1H), 4.15 (t, J = 5.8 Hz, 2H), 3.68-3.61 (m, 1H), 2.84 (t, J = 5.8 Hz, 2H), 2.64 (brs, 4H), 2.49 (brs, 4H), 2.30 LCMS C 24 H 34 N4OS method (B) R t = 4.535 points, ESI+ m / z = 427.3 (M+H).

[0220] 1-(4-メチル-4'-(2-(4-メチルピペラジン-1-イル)-2-オキソエトキシ)-[1,1' -ビフェニル]-3-イル)-1-プロピルチオurea OR0597-2 (method A, 47%), white solid として. 1 H NMR (400 MHz, CDCl3) δ 7.49 (dd, J = 8.0, 1.9 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H), 7.39 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 1.9 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 5.50 (brs, 2H), 4.73 (s, 2H), 3.67-3.56 (m, 4H), 2.44-2.36 (m, 4H), 2.29 (s, 3H), 2.25 (s, 3H), 1.86-1.74 (m, 1H), 1.74-1.62 (m, 1H), 0.91 (t, J = 7.4 Hz, 3H); LCMS C 24 H 32N4O2S method (B) R t = 4.498 min, ESI+ m / z = 441.3 (M+H).

[0221] 1-(2-Methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethyl)pyridin-3-yl)phenyl)-1-propylthiourea OR0599-2 (Method A, 81%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 2.0 Hz, 1H), 7.74 (dd, J = 8.0, 2.0 Hz, 1H), 7.52 (dd, J = 8.0, 2.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 5.53 (brs, 2H), 4.48-4.41 (m, 1H), 3.69-3.61 (m, 1H), 3.05-3.01 (m, 2H), 2.81-2.77 (m, 2H), 2.59 (brs, 4H), 2.48 (brs, 4H), 2.29 (s, 3H), 2.28 (s, 3H), 1.82-1.63 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H); LCMS C 23 H 33 N5S method (B) R t = 3.891 min, ESI+ m / z = 412.3 (M+H).

[0222] General procedure for the synthesis of N-([1,1'-biaryl]-3-ylcarbamothioyl)acetamide derivatives. As previously described for N-((3-nitroaryl)carbamothioyl)acetamide derivatives.

[0223] N-((4-methyl-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-3-yl)carbamothioyl)acetamide OR0274-3 (Method A, 67%) as a light brown solid was used in the next step without further purification.

[0224] N-((4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)carbamothioyl)acetamide OR0325-3 (Method A, 83%) as a light brown solid was used in the next step without further purification.

[0225] N-((4'-hydroxy-4-methyl-[1,1'-biphenyl]-3-yl)carbamothioyl)acetamide OR0320-3 (72%) as a white solid. 1 H NMR (400 MHz, MeOD) δ 7.88 (d, J = 1.9 Hz, 1H), 7.45 (d, J = 8.7 Hz, 2H), 7.39 (dd, J = 7.9, 1.9 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 6.83 (d, J = 8.7 Hz, 2H), 2.27 (s, 3H), 2.18 (s, 3H); LCMS C 16 H 16 N2O2S method (A) R t = 6.114 min, ESI+ m / z = 301.0 (M+H).

[0226] N-((4'-hydroxy-3'-methoxy-4-methyl-[1,1'-biphenyl]-3-yl)carbamothioyl)acetamide OR0321-3 (Method A, 88%) as a light brown solid. 1 H NMR (400 MHz, MeOD) δ 7.90 (d, J = 1.8 Hz, 1H), 7.41 (dd, J = 7.9, 1.8 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.06 (dd, J LCMS C 17 H 18 N2O3S method (A) R t = 6.215 min, ESI+ m / z = 331.1 (M+H).

[0227] General procedure for the synthesis of N-([1,1'-biaryl]-3-ylcarbamothioyl)benzamide derivatives. Benzoyl isothiocyanate (1.1 mmol) was added dropwise to a solution of the appropriate [1,1'-biaryl]-3-N-alkylamine (1.0 mmol) in dry acetone (25 mL) at 0°C under argon. The resulting solution was stirred at 0°C for an additional 1 h and then warmed to room temperature. After stirring overnight, upon complete consumption of the starting material as monitored by TLC and LCMS, the solvent was evaporated under reduced pressure. The crude residue of the corresponding N-([1,1'-biaryl]-3-ylcarbamothioyl)benzamide was used in the next step without further purification.

[0228] N-((4-methyl-4'-(3-(4-methylpiperazin-1-yl)propyl)-[1,1'-biphenyl]-3-yl)(propyl)carbamothioyl)benzamide OR0598-3 (quantitative) as a pale yellow solid. Rf=0.40 (DCM-MeOH-NH4OH, 90:9:1); 1 H NMR (400 MHz, CDCl3) δ 7.57-7.20 (m, 12H), 4.48-4.42 (m, 1H), 3.86-3.80 (m, 1H), 2.72-2.64 (m, 2H), 2.58 (brs, 8H), 2.48-2.40 (m, 2H), 2.35 (s, 3H), 2.33 (s, 3H), 1.91-1.71 (m, 4H), 0.95 (t, J = 7.4 Hz, 3H); LCMS C 32 H 40 N4OS method (B) R t = 4.647 min, ESI+ m / z = 529.3 (M+H).

[0229] N-(8-(4-(2-(4-methylpiperazin-1-yl)ethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carbonothioyl)benzamide OR0402-3 (96%) as a pale yellow solid, used in the next step without further purification; LCMS C 31H 36 N4OS, Method (B)R t =3.787 min, ESI+m / z=513.3(M+H).

[0230] N-((4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethoxy)-[1,1'-biphenyl]-3-yl)(propyl)carbamothioyl)benzamide OR0596-3 (99%) as a pale yellow solid. Rf=0.36 (DCM-MeOH-NH4OH, 90:9:1); LCMS C 31 H 38 N4O2S, method (B)R t =4.982 min, ESI+m / z=531.3(M+H).

[0231] N-((4-methyl-4'-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy)-[1,1'-biphenyl]-3-yl)(propyl)carbamothioyl)benzamide OR0597-3 (quantitative) as a white solid. Rf=0.42 (DCM-MeOH-NH4OH, 90:9:1); LCMS C 31 H 36 N4O3S, method (B)R t =4.907 min, ESI+m / z=545.3(M+H).

[0232] N-((2-methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethyl)pyridin-3-yl)phenyl)(propyl)carbamothioyl)benzamide OR0599-3 (quantitative) was used in the next step without further purification as a white solid. Rf=0.40 (DCM-MeOH-NH4OH, 90:9:1); LCMS C 30 H 37 N5OS, Method (B)R t =4.461 min, ESI+m / z=516.3(M+H).

[0233] General procedure for the synthesis of [1,1'-biaryl]-3-N-alkylamine derivatives. To a stirred solution of the appropriate [1,1'-biaryl]-3-amine (1.0 mmol) and aldehyde (1.5 mmol) in anhydrous tetrahydrofuran (8 mL), glacial acetic acid (1.5 mmol) was added dropwise. After stirring for 2 h, sodium triacetoxyborohydride (2.7 mmol) was added portionwise. The resulting suspension was stirred at room temperature until complete consumption of the starting material, as monitored by TLC and LCMS. The reaction was carefully quenched with a saturated aqueous solution of Na2CO3 (20 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried over Na2SO4, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography to give the corresponding [1,1'-biaryl]-3-N-alkylamine.

[0234] 4-Methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-N-propyl-[1,1'-biphenyl]-3-amine OR0345-3 (71%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H), 7.10 (d, J = 7.6 Hz, 1H), 6.85 (dd, J = 7.6, 1.7 Hz, 1H), 6.79 (d, J = 1.7 Hz, 1H), 3.19 (t, J = 7.1 Hz, 2H), 2.89-2.81 (m, 2H), 2.69-2.62 (m, 2H), 2.51 (brs, 8H), 2.32 (s, 3H), 2.17 (s, 3H), 1.73 (sextet, J = 7.4 Hz, 2H), 1.03 (t, J = 7.4 Hz, 3H); LCMS C 23 H 33 N3 method (B) R t = 4.429 min, ESI+ m / z = 352.3 (M+H).

[0235] 4-Methyl-4'-(3-(4-methylpiperazin-1-yl)propyl)-N-propyl-[1,1'-biphenyl]-3-amine OR0598-4 (64%) as a yellow foam. Rf=0.38 (DCM-MeOH-NH4OH, 90:9:1); 1 H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 7.10 (d, J = 7.7 Hz, 1H), 6.86 (dd, J = 7.7, 1.7 Hz, 1H), 6.80 (d, J = 1.7 Hz, 1H), 3.52 (brs, 1H), 3.20 (t, J = 7.1 Hz, 2H), 2.69-2.65 (m, 2H), 2.49 (brs, 8H), 2.43-2.39 (m, 2H), 2.31 (s, 3H), 2.17 (s, 3H), 1.86 (quintet, J = 7.7 Hz, 2H), 1.72 (sextet, J = 7.4 Hz, 2H), 1.04 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 146.57, 140.76, 140.30, 139.76, 130.32, 128.62, 127.06, 120.70, 115.46, 108.44, 58.01, 55.10, 53.09, 46.00, 45.81, 33.37, 28.61, 22.79, 17.15, 11.75; LCMS C 24 H 35 N3 method (B) R t = 4.475 min, ESI+ m / z = 366.3 (M+H).

[0236] 4-Methyl-4'-(2-(4-methylpiperazin-1-yl)ethoxy)-N-propyl-[1,1'-biphenyl]-3-amine OR0596-4 (63%) as a pale yellow solid. Rf=0.36 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 7.8 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.82 (dd, J = 7.8, 1.8 Hz, 1H), 6.77 (d, J = 1.8 Hz, 1H), 4.15 (t, J = 5.9 Hz, 2H), 3.52 (brs, 1H), 3.19 (t, J = 7.1 Hz, 2H), 2.84 (t, J = 5.9 Hz, 2H), 2.64 (brs, 4H), 2.50 (brs, 4H), 2.30 (s, 3H), 2.16 (s, 3H), 1.72 (sextet, J = 7.4 Hz, 2H), 1.04 (t, J = 7.4 Hz, 3H); LCMS C 23 H 33 N3O method (B) R t = 4.536 points, ESI+ m / z = 368.3 (M+H).

[0237] 2-((4'-メチル-3'-(プロピルアミノ)-[1,1'-ビフェニル]-4-イル)オキシ)-1 -(4-メチルピペラジン-1-イル)エタン-1-オンOR0597-4 (82%), colorless oily substance. 1 H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 7.6 Hz, 1H), 6.99 (d, J = 8.8 Hz, 2H), 6.81 (dd, J = 7.6, 1.7 Hz, 1H), 6.76 (d, J = 1.7 Hz, 1H), 4.72 (s, 2H), 3.71-3.59 (m, 4H), 3.19 (t, J = 7.4 Hz, 2H), 2.46-2.35 (m, 4H), 2.30 (s, 3H), 2.16 (s, 3H), 1.72 (sexeter, J = 7.4 Hz, 2H), 1.04 (t, J = 7.4 Hz, 3H); LCMS C 23 H 31 N3O2 method (B) R t= 4.433 min, ESI+ m / z = 382.3 (M+H).

[0238] 2-Methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethyl)pyridin-3-yl)-N-propylaniline OR0599-4 (71%) as a colorless oil. Rf=0.38 (DCM-MeOH-NH4OH, 90:9:1); 1 H NMR (400 MHz, CDCl3) δ 8.74 (d, J = 1.8 Hz, 1H), 7.77 (dd, J = 8.0, 2.4 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 7.7 Hz, 1H), 6.82 (dd, 2.61 (brs, 4H), 2.49 (brs, 4H), 2.30 (s, 3H), 2.17 (s, 3H), 1.73 (sextet, J = 7.4 Hz, 2H), 1.03 (t, J = 7.4 Hz, 3H); LCMS C 22 H 32 N4 method (B) R t = 3.941 min, ESI+ m / z = 353.3 (M+H).

[0239] General procedure for the synthesis of [1,1'-biaryl]-3-amine derivatives. Under a hydrogen atmosphere, a solution of the appropriate 3-nitro-1,1'-biaryl (1 mmol) and a mixture of 10% palladium on carbon (10% w / w) in tetrahydrofuran-ethanol (1:1, 20 mL) was stirred at room temperature until the reaction was complete, as indicated by TLC monitoring. The reaction mixture was filtered through a short Celite pad and rinsed with EtOH. The solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography to give the corresponding [1,1'-biaryl]-3-amine.

[0240] 4-Methyl-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-3-amine OR0274-4 (52%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.11 (d, J = 7.7 Hz, 1H), 6.94 (dd, J = 7.7, 1.8 Hz, 1H), 6.90 (d, J = 1.7 Hz, 1H), 6.90 (d, J = 1.7 Hz, 1H), 3.67 (brs, 2H), 3.54 (s, 2H), 2.49 (s, 8H), 2.30 (s, 3H), 2.21 (s, 3H).

[0241] 4-Methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-amine OR0325-4 (95%), as a white powder. 1 H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 7.10 (d, J = 7.7 Hz, 1H), 6.92 (dd, J = 7.7, 1.8 Hz, 1H), 6.89 (d, LC method (C) R t = 2.077 minutes.

[0242] 3'-Amino-4'-methyl-[1,1'-biphenyl]-4-ol OR0320-4 (quantitative), as a yellow oil, without further purification. 1H NMR (400 MHz, MeOD) δ 7.38 (d, J = 8.7 Hz, 2H), 7.00 (d, J = 7.7 Hz, 1H), 6.93 (d, J = 1.7 Hz, 1H), 6.82 (dd, J = 7.7, 1.7 Hz, 1H), 6.80 (d, J = 8.7 Hz, 2H), 2.17 (s, 3H); LCMS C 13 H 13 NO method (A) R t = 5.325 min, ESI+ m / z = 200.2 (M+H).

[0243] 3'-Amino-3-methoxy-4'-methyl-[1,1'-biphenyl]-4-ol OR0321-4 (81%), as a white powder. 1 H NMR (400 MHz, CDCl3) δ 7.10-7.04 (m, 3H), 6.95 (d, J = 8.0 Hz, 1H), 6.89 (dd, J = 7.7, 1.8 Hz, 1H), 6.86 (d, J = 1.8 Hz, 1H), 5.59 (s, 1H), 3.94 (s, 3H), 3.67 (brs, 2H), 2.20 (s, 3H); LCMS C 14 H 15 NO2 method (A) R t = 5.721 min, ESI+ m / z = 230.2 (M+H).

[0244] 4-Methyl-4'-(3-(4-methylpiperazin-1-yl)propyl)-[1,1'-biphenyl]-3-amine OR0598-5 (86%) as a yellow foam. Rf=0.35 (DCM-MeOH-NH4OH, 90:9:1). 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 7.10 (d, J = 7.7 Hz, 1H), 6.93 (dd, J = 7.7, 1.8 Hz, 1H), 6.89 (d, J = 1.8 Hz, 1H), 3.66 (brs, 2H), 2.68-2.63 (m, 2H), 2.48 (brs, 8H), 2.42-2.38 (m, 2H), 2.29 (s, 3H), 2.20 (s, 3H), 1.85 (quintet, J = 7.7 Hz, 2H); LCMS C 21 H 29 N3 method (B) R t = 3.659 min, ESI+ m / z = 324.3 (M+H).

[0245] 4-Methyl-4'-(2-(4-methylpiperazin-1-yl)ethoxy)-[1,1'-biphenyl]-3-amine OR0596-5 (quantitative) as a yellow oil. LCMS C 20 H 27 N3O, method (B)R t =3.669 min, ESI+m / z=326.3(M+H).

[0246] 2-((3'-amino-4'-methyl-[1,1'-biphenyl]-4-yl)oxy)-1-(4-methylpiperazin-1-yl)ethan-1-one OR0597-5 (quantitative) as a pink solid. LCMS C 20 H 25 N3O2, method (B)R t =3.586 min, ESI+m / z=340.4(M+H).

[0247] 2-Methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethyl)pyridin-3-yl)aniline OR0599-5 (76%) as a white solid, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 2.0 Hz, 1H), 7.74 (dd, J = 8.0, 2.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H), 6.89 (dd, J = 7.7, 2.0 Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H), 3.72 (brs, 2H), 3.04-3.02 (m, 2H), 2.83-2.81 (m, 2H), 2.64 (brs, 4H), 2.53 (brs, 4H), 2.32 (s, 3H), 2.20 (s, 3H); LCMS C 19 H 26 N4 method (B) R t = 1.680 min, ESI+ m / z = 311.2 (M+H).

[0248] 8-(4-(2-(4-methylpiperazin-1-yl)ethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine OR0402-4. A suspension of a mixture of 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)piperazine OR0402-5 (330 mg, 1.0 mmol), 8-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azepine hydrochloride (262 mg, 1.0 mmol), PdCl(dppf) (109 mg, 0.149 mmol), and KCO (839 mg, 6.07 mmol) in 1,4-dioxane-water (5:1, 30 mL) was thoroughly degassed several times under an argon blanket. The reaction mixture was heated at 80 °C for 1.5 h. The solvent was evaporated, and the residue was triturated with EtOAc-DCM (1:1, 250 mL) and filtered through a Celite pad. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography, gradient DCM-MeOH-NH4OH (100:0:0 to 90:9:1) to give 8-(4-(2-(4-methylpiperazin-1-yl)ethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine OR0402-4 (215 mg, 61%) as a yellow foam. Rf=0.27 (DCM-MeOH-NH4OH, 95:5:0.5); 1 H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H), 7.16 (d, J = 7.7 Hz, 1H), 7.04 (dd, J = 7.7, 1.8 Hz, 1H), 6.94 (d, J = 1.8 Hz, 1H), 3.88 (brs, 1H), 3.12-3.06 (m, 2H), 2.87-2.83 (m, 2H), 2.82-2.78 (m, 2H), 2.70-2.64 (m, 2H), 2.60 (brs, 8H), 2.35 (s, 3H), 1.85-1.81 (m, 2H), 1.70-1.66 (m, 2H).). 13C NMR (100 MHz, CDCl3) δ 150.79, 139.67, 139.09, 139.05, 132.76, 131.38, 129.11, 127.11, 119.56, 118.02, 60.44, 55.10, 53.03, 49.06, 46.01, 35.85, 33.27, 32.10, 27.10; LCMS C 23 H 31 N3 method (B) R t = 2.662 min, ESI+ m / z = 350.3 (M+H).

[0249] General procedure for the synthesis of 3-nitro-1,1'-biaryl derivatives. Under argon, a suspension of the appropriate aryl halide (1.0 mmol), 4,4,5,5-tetramethyl-2-(4-methyl-3-nitrophenyl)-1,3,2-dioxaborolane (264 mg, 1.03 mmol), PdCl(dppf) (36 mg, 0.05 mmol), and NaCO (212 mg, 2 mmol) in a degassed mixture of 1,4-dioxane and water (5:1, 12 mL) was refluxed for 3 h until the starting material was completely consumed. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography to give the corresponding 3-nitro-1,1'-biaryl.

[0250] 1-Methyl-4-(4'-methyl-3'-nitro-[1,1'-biphenyl]-4-yl)methyl)piperazine OR0274-5 (74%) as a dark oil. 1 H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 1.9 Hz, 1H), 7.71 (dd, J = 8.0, 1.9 Hz, 1H), 7.54 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H), 7.39 (d, LC method (A) R t = 6.840 minutes.

[0251] 1-Methyl-4-(2'(4'-methyl-3'-nitro-[1,1'-biphenyl]-4-yl)ethyl)piperazine OR0325-5 (89%) as a dark oil. 1 H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 1.9 Hz, 1H), 7.70 (dd, J = 7.9, 1.9 Hz, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 7.9 Hz, 1H), 7.31 (d, LCMS C 20 H 25 N3O2 method (B) R t = 4.532 min, ESI+ m / z = 340.2 (M+H).

[0252] 4'-Methyl-3'-nitro-[1,1'-biphenyl]-4-ol OR0320-5 (73%), as a yellow powder. 1 H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 2.0 Hz, 1H),), 7.67 (dd, J = 7.9, 2.0 Hz, 1H), 7.49 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 7.9 Hz, 1H), 6.93 (d, J = 8.7 Hz, 2H), 4.94 (s, 1H), 2.62 (s, 3H); LCMS C 13 H 11 NO3 method (A) R t = 6.516 min, ESI+ m / z = 230.1 (M+H).

[0253] 3-Methoxy-4'-methyl-3'-nitro-[1,1'-biphenyl]-4-ol OR0321-5 (69%) as a yellow powder. 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 1.6 Hz, 1H), 7.67 (dd, J = 7.9, 1.6 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.11 (dd, J = 8.2, 1.9 Hz, 1H), 7.06 (d, J = 1.9 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 5.71 (s, 1H), 3.98 (s, 3H), 2.62 (s, 3H); LCMS C 14 H 13 NO4 method (A) R t = 6.637 min, ESI+ m / z = 260.1 (M+H).

[0254] 1-Methyl-4-(3'(4'-methyl-3'-nitro-[1,1'-biphenyl]-4-yl)propyl)piperazine OR0598-6 (73%) as a yellow foam. Rf=0.42 (DCM-MeOH-NH4OH, 90:9:1). 1 H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 1.9 Hz, 1H), 7.70 (dd, J = 7.9, 1.9 Hz, 1H), 7.51 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.0 Hz, 1H), 7.28 (d, LCMS C 21 H 27 N3O2 method (B) R t = 4.576 min, ESI+ m / z = 354.2 (M+H).

[0255] 1-Methyl-4-(2-((4'-methyl-3'-nitro-[1,1'-biphenyl]-4-yl)oxy)ethyl)piperazine OR0596-6 (72%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 2.0 Hz, 1H), 7.67 (dd, J = 8.0, 2.0 Hz, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.0 Hz, 1H), 6.99 (d, LCMS C 20 H 25 N3O3 method (B) R t = 4.655 min, ESI+ m / z = 356.3 (M+H).

[0256] 2-((4'-methyl-3'-nitro-[1,1'-biphenyl]-4-yl)oxy)-1-(4-methylpiperazin-1-yl)ethan-1-one OR0597-6 (72%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 1.8 Hz, 1H), 7.66 (dd, J = 7.9, 1.8 Hz, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 7.9 Hz, 1H), 7.04 (d, LCMS C 20 H 23 N3O4 method (B) R t = 4.555 min, ESI+ m / z = 370.4 (M+H).

[0257] 1-Methyl-4-(2-(5-(4-methyl-3-nitrophenyl)pyridin-2-yl)ethyl)piperazine OR0599-6 (79%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 1.9 Hz, 1H), 7.80 (dd, J = 8.1, 2.4 Hz, 1H), 7.70 (dd, J = 7.9, 1.9 Hz, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 3.06-3.03 (m, 2H), 2.82-2.80 (m, 2H), 2.64 (s, 3H), 2.60 (brs, 4H), 2.48 (brs, 4H), 2.29 (s, 3H); LCMS C 19 H 24 N4O2 method (B) R t = 3.942 min, ESI+ m / z = 341.2 (M+H).

[0258] General procedure for the synthesis of 1-(arylalkyl)-4-methylpiperazine derivatives. Under argon, potassium carbonate (4.13 g, 30 mmol) and N-methyl-piperazine (1.40 mL, 15 mmol) were added sequentially to a solution of the appropriate arylalkyl methanesulfonate (10 mmol) in acetonitrile (30 mL). The reaction mixture was heated at 60 °C until complete conversion was monitored by TLC. The resulting mixture was cooled to room temperature and then poured into HO (100 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine and dried over NaSO. The solvent was evaporated, and the residue was purified by flash chromatography to give the corresponding 1-(arylalkyl)-4-methylpiperazine.

[0259] 1-(4-Bromophenethyl)-4-methylpiperazine OR0325-6 (68%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 8.3 Hz, 2H), 2.79-2.71 (m, 2H), 2.62-2.54 (m, 2H), 2.53 (brs, 8H), 2.32 (s, 3H). LC method (D) R t = 5.648 minutes.

[0260] 1-(3-(4-bromophenyl)propyl)-4-methylpiperazine OR0598-7 (98%) was used in the next step without further purification, Rf=0.40 (DCM-MeOH-NH4OH, 90:9:1). 1 H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 2.62-2.54 (m, 2H), 2.44 (brs, 8H), 2.38-2.30 (m, 2H), 2.28 (s, 3H), 1.78 (quintet, J = 7.7 Hz, 2H); LCMS C 14 H 21 BrN2 method (B) R t = 1.174 min, ESI+ m / z = 297.1 (M+H).

[0261] 1-(2-(5-bromopyridin-2-yl)ethyl)-4-methylpiperazine OR0599-7 (81%) was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 2.2 Hz, 1H), 7.69 (dd, J = 8.3, 2.2 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 2.96-2.88 (m, 2H), 2.76-2.68 (m, 2H), 2.54 (brs, 4H), 2.43 (brs, 4H), 2.27 (s, 3H); LCMS C 12 H 18 BrN3 method (B) R t = 1.921 min, ESI+ m / z = 284.0 (M+H).

[0262] 1-(2-(4-Bromophenoxy)ethyl)-4-methylpiperazine OR0596-7 (88%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 9.0 Hz, 2H), 6.78 (d, J = 9.0 Hz, 2H), 4.06 (t, J = 5.8 Hz, 2H), 2.79 (t, J = 5.8 Hz, 2H), 2.60 (brs, 4H), 2.47 (brs, 4H), 2.28 (s, 3H); LCMS C 13 H 19 BrN2O method (B) R t = 4.004 min, ESI+ m / z = 299.1 (M+H).

[0263] 1-Methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)piperazine OR0402-5 (65%) as a white solid. Rf=0.40 (EP / EA, 5:5); 1 H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 2.86-2.78 (m, 2H), 2.67-2.59 (m, 2H), 2.61 (brs, 8H), 2.34 (s, 3H), 1.33 (s, 12H); 13 C NMR (100 MHz, CDCl3) δ 143.63, 135.09, 128.27, 83.82, 60.11, 55.00, 52.81, 45.89, 33.78, 24.98; 19 H 31 BN2O2 method (B) R t = 3.392 min, ESI+ m / z = 331.3 (M+H).

[0264] 2-(4-Bromophenoxy)-1-(4-methylpiperazin-1-yl)ethan-1-one OR0597-7. via peptide coupling procedures previously described for the synthesis of di-tert-butyl (2-(2-((3-benzamidoaryl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate derivatives (88%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 9.1 Hz, 2H), 6.83 (d, J = 9.1 Hz, 2H), 4.66 (s, 2H), 3.66-3.60 (m, 2H), 3.59-3.53 (m, 2H), 2.41-2.33 (m, 4H), 2.28 (s, 3H); LCMS C 13 H 17 BrN2O2 method (B) R t = 3.939 min, ESI+ m / z = 313.1 (M+H).

[0265] General procedure for the synthesis of 1-(arylalkyl)methanesulfonate derivatives. Under argon, methanesulfonyl chloride (1.15 mL, 14.9 mmol) was added dropwise to a solution of the appropriate commercially available alcohol (10 mmol) and triethylamine (2.8 mL, 20 mmol) in dry dichloromethane (30 mL) at −5° C. After the addition, the reaction mixture was stirred at −5° C. for 45 min until complete conversion was monitored by TLC, then poured into saturated aqueous NaHCO (50 mL) and extracted twice with DCM (20 mL). The combined organic layers were washed with brine and dried over NaSO. The solvent was evaporated to give the corresponding arylalkyl methanesulfonate, which was used in the next step without further purification.

[0266] 4-Bromophenethyl methanesulfonate OR0325-7 (quantitative), as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 4.39 (t, J = 6.8 Hz, 2H), 3.01 (t, J = 6.8 Hz, 2H), 2.89 (s, 3H); LCMS C9H 11BrO3S method (B) R t = 6.025 min, ESI+ m / z = 301.0 (M+Na).

[0267] 3-(4-Bromophenyl)propyl methanesulfonate OR0598-8 (95%) as a white solid. Rf=0.55 (DCM). 1 H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 4.21 (t, J = 6.3 Hz, 2H), 2.99 (s, 3H), 2.75-2.67 (m, 2H), 2.10-1.99 (m, 2H); LC method (B) R t = 5.642 minutes.

[0268] 2-(4-Bromophenoxy)ethyl methanesulfonate OR0596-8 (quantitative) as a colorless oil. LC, Method (B)R t =6.010 minutes.

[0269] 2-(5-Bromopyridin-2-yl)ethyl methanesulfonate OR0599-8 (quantitative) was used in the next step without further purification as a colorless oil. LCMS C8H 10 BrNO3S, method (B)R t =5.280 min, ESI+m / z=280.0(M+H).

[0270] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl methanesulfonate OR0402-6 (91%) as a white solid, used in the next step without further purification, Rf=0.30 (PE / EtOAc, 1:1); 1 H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.9 Hz, 2H), 7.24 (d, J = 7.9 Hz, 2H), 4.42 (t, J = 6.9 Hz, 2H), 3.06 (t, J = 6.9 Hz, 2H), 2.83 (s, 3H), 1.34 (s, 12H); LCMS C15 H 23 BO5S method (B) R t = 5.498 points, ESI+ m / z = 327.2 (M+H).

[0271]

change

[0272] Reagents and conditions: i) Boc2O, DMAP; ii) Tribune (1-Ethylene Glycol) Sus, Pd(PPh3)2Cl2, CsF, CuBr; iii) NBS; iv) 4-CHOAr-≡, PdCl2(PPh3)2, CuI, PPh3, TEA; v) Amino, NaBH(OAc)3, AcOH; vi) SnCl2.H2O, THF-EtOH; vii) KSCN, AcCl; viiii) K2CO3, MeOH; ix) K2CO3, EtOH; ix) TFA.

[0273] 4-(4-aminopyrimidin-2-yl)-N-(3-(arylethynyl)aryl)thiazol-2-amine derivatives were prepared by a convergent synthesis from commercially available 4-amino-2-chloropyrimidines and the appropriate bromo-3-nitrobenzenes (Scheme 3). 4-Amino-2-chloropyrimidines were protected using BocO to give the corresponding bis-carbamates. Stille cross-coupling with tributyl(1-ethoxyvinyl)tin afforded the enol ethers, which were then transformed into the corresponding α-bromoketones using N-bromosuccinimide. Starting from the appropriate bromo-3-nitrobenzenes, Sonogashira cross-coupling with the appropriate 4-ethynylbenzaldehydes allowed the introduction of key 1,2-diarylethyne scaffolds. Reductive amination afforded the corresponding benzylamine, while reduction of the nitro group followed by condensation with acetylisothiocyanate and saponification afforded the corresponding thiourea. The thiourea was then used with α-bromoketones in the Hantzsch thiazole synthesis to give the corresponding thiazole. Finally, deprotection with TFA afforded the expected 4-(4-aminopyrimidin-2-yl)-N-(3-(arylethynyl)aryl)thiazol-2-amine.

[0274] General procedure for the synthesis of 4-(4-aminopyrimidin-2-yl)-N-(3-(arylethynyl)aryl)thiazol-2-amine derivatives. As previously described for N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-aryl)benzamide derivatives.

[0275] 4-(4-aminopyrimidin-2-yl)-N-(5-((4-((dimethylamino)methyl)phenyl)ethynyl)-2-methylphenyl)thiazol-2-amine OR0237 (30%) as a white powder. 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 5.8 Hz, 1H), 7.67 (d, J = 1.2 Hz, 1H), 7.60 (s, 1H), 7.50 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.24 (dd, J = 7.8, 1.2 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 6.34 (d, J = 5.8 Hz, 1H), 4.98 (s, 2H), 3.43 (s, 2H), 2.32 (s, 3H), 2.24 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ 166.21, 163.10, 160.53, 156.60, 150.57, 139.37, 138.76, 131.71, 131.45, 130.23, 129.24, 128.02, 123.03, 122.49, 121.96, 111.40, 103.46, 89.63, 88.85, 64.23, 45.49, 18.11; LC method (D) R t = 4.030 minutes.

[0276] 4-(4-aminopyrimidin-2-yl)-N-(2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)phenyl)ethynyl)phenyl)thiazol-2-amine OR0153 (45%) as a white powder. 1 H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 5.7 Hz, 1H), 7.67 (d, J = 1.2 Hz, 1H), 7.60 (s, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.24 (dd, J = 7.8, 1.2 Hz, 1H), 7.22 (d, J = 8.0 Hz), 6.34 (d, J = 5.7 Hz, 1H), 4.98 (s, 2H), 3.51 (s, 2H), 2.47 (brs, 8H), 2.32 (s, 3H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.37, 163.13, 160.55, 156.55, 150.59, 138.84, 131.65, 131.45, 130.48, 129.24, 128.10, 123.30, LC method (D) R t = 3.865 minutes.

[0277] General procedure for the synthesis of di-tert-butyl (2-(2-((3-(arylethynyl)aryl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate derivatives. As previously described for di-tert-butyl (2-(2-((3-nitroaryl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate derivatives.

[0278] Di-tert-butyl (2-(2-((5-((4-((dimethylamino)methyl)phenyl)ethynyl)-2-methylphenyl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0237-1 (60%) as a light brown powder. 1 H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 5.7 Hz, 1H), 7.67 (d, J = 1.3 Hz, 1H), 7.53 (d, J = 5.1 Hz, 1H), 7.53 (s, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 7.26 (dd, J = 7.8, 1.3 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 3.47 (s, 2H), 2.32 (s, 3H), 2.27 (s, 6H), 1.56 (s, 18H).

[0279] Di-tert-butyl (2-(2-((2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)phenyl)ethynyl)phenyl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0153-1 (44%) as a light brown powder. 1 H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 5.7 Hz, 1H), 7.67 (d, J = 1.4 Hz, 1H), 7.53 (d, J = 5.9 Hz, 1H), 7.53 (s, 1H), 7.48 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 7.25 (dd, J = 7.9, 1.4 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 3.53 (s, 2H), 2.55 (brs, 8H), 2.36 (s, 3H), 2.32 (s, 3H), 1.56 (s, 18H).

[0280] General procedure for the synthesis of 1-(3-(arylethynyl)aryl)thiourea derivatives. As previously described for 1-(3-nitroaryl)thiourea derivatives.

[0281] 1-(5-((4-((dimethylamino)methyl)phenyl)ethynyl)-2-methylphenyl)thiourea OR0237-2 (72%), as a white powder. 1 H NMR (400 MHz, MeOD) δ 7.53-7.47 (m, 3H), 7.40-7.30 (m, 4H), 3.50 (s, 2H), 2.30 (s, 3H), 2.25 (s, 6H).

[0282] 1-(2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)phenyl)ethynyl)phenyl)thiourea OR0153-2 (65%), as a white powder. 1 H NMR (400 MHz, MeOD) δ 7.53-7.21 (m, 7H), 3.55 (s, 2H), 2.51 (brs, 8H), 2.28 (s, 6H).

[0283] General procedure for the synthesis of N-((3-(arylethynyl)aryl)carbamothioyl)acetamide derivatives. As previously described for N-((3-nitroaryl)carbamothioyl)acetamide derivatives.

[0284] N-((5-((4-((dimethylamino)methyl)phenyl)ethynyl)-2-methylphenyl)carbamothioyl)acetamide OR0237-3, a light brown solid, was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 12.01 (s, 1H), 9.10 (s, 1H), 7.86 (d, J = 1.3 Hz, 1H), 7.57 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H), 7.39 (dd, J = 7.9, 1.3 Hz, 1H), 7.24 (d, J = 7.9 Hz, 1H), 4.09 (s, 2H), 2.70 (s, 6H), 2.32 (s, 3H), 2.26 (s, 3H).

[0285] N-((2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)phenyl)ethynyl)phenyl)carbamothioyl)acetamide OR0153-3, a light brown solid, was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 11.99 (s, 1H), 9.07 (s, 1H), 7.83 (d, J = 1.3 Hz, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.37 (dd, J = 7.8, 1.3 Hz, 1H), 7.28 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 7.8 Hz, 1H), 3.60 (s, 2H), 2.90 (brs, 8H), 2.66 (s, 3H), 2.31 (s, 3H), 2.25 (s, 3H).

[0286] General procedure for the synthesis of 3-(arylethynyl)aniline derivatives. As previously described for di-tert-butyl (2-(2-((3-aminoaryl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate derivatives.

[0287] 5-((4-((dimethylamino)methyl)phenyl)ethynyl)-2-methylaniline OR0237-4, used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.01 (d, J = 7.7 Hz, 1H), 6.88 (dd, J = 7.7, 1.9 Hz, 1H), 6.85 (d, J = 1.9 Hz, 1H), 3.62 (brs, 2H), 3.50 (s, 2H), 2.46 (s, 2H), 2.25 (s, 6H), 2.18 (s, 3H).

[0288] 2-Methyl-5-((4-((4-methylpiperazin-1-yl)methyl)phenyl)ethynyl)aniline OR0153-4, used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.01 (d, J = 7.7 Hz, 1H), 6.88 (dd, J = 7.7, 1.1 Hz, 1H), 6.85 (d, J = 1.1 Hz, 1H), 3.62 (brs, 2H), 3.50 (s, 2H), 2.46 (brs, 8H), 2.29 (s, 3H), 2.18 (s, 3H).

[0289] General procedure for the synthesis of (4-((3-nitroaryl)ethynyl)aryl)methanamine derivatives. To a solution of a mixture of the appropriate 4-((3-nitroaryl)ethynyl)benzaldehyde (1 mmol) and amine (3 mmol) in 1,2-dichloroethane-tetrahydrofuran (10:1, 11 mL) was added a few drops of acetic acid. The reaction mixture was stirred for 5 min, and then sodium triacetoxyborohydride (424 mg, 2 mmol) was added portionwise. The resulting suspension was stirred at room temperature overnight upon complete consumption of the starting material, as monitored by TLC. The reaction was slowly quenched with saturated aqueous NaHCO3 (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography to give the corresponding (4-((3-nitroaryl)ethynyl)aryl)methanamine.

[0290] N,N-Dimethyl-1-(4-((4-methyl-3-nitrophenyl)ethynyl)phenyl)methanamine OR0237-5 (51%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 1.6 Hz, 1H), 7.61 (dd, J = 7.9, 1.6 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.33-7.31 (m, 3H), 3.44 (s, 2H), 2.61 (s, 3H), 2.25 (s, 6H).

[0291] 1-Methyl-4-(4-((4-methyl-3-nitrophenyl)ethynyl)benzyl)piperazine OR0153-5 (53%) as a light brown powder. 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 1.7 Hz, 1H), 7.61 (dd, J = 7.9, 1.7 Hz, 1H), 7.48 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 7.9 Hz, 1H), 3.52 (s, 2H), 2.61 (s, 3H), 2.49 (brs, 8H), 2.31 (s, 3H).

[0292] General procedure for the synthesis of 4-((3-nitroaryl)ethynyl)benzaldehyde derivatives. A solution of a mixture of the appropriate bromo-3-nitrobenzene (1 mmol) and 4-ethynylbenzaldehyde (1.4 mmol) in dimethylformamide-triethylamine (1:1, 6 mL) was thoroughly degassed several times under an argon atmosphere. Bis(triphenylphosphine)palladium(II) dichloride (35 mg, 0.05 mmol), copper iodide (10 mg, 0.05 mmol), and triphenylphosphine (26 mg, 0.1 mmol) were added sequentially. The reaction mixture was heated at 70 °C until complete conversion was monitored by TLC. The solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography to give the corresponding 4-((3-nitroaryl)ethynyl)benzaldehyde.

[0293] 4-((4-methyl-3-nitrophenyl)ethynyl)benzaldehyde OR0153-6 (quantitative), as a light brown powder. 1 H NMR (400 MHz, CDCl3) δ 10.03 (s, 1H), 8.15 (d, J = 1.6 Hz, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 8.2 Hz, 2H), 7.65 (dd, J = 7.9, 1.6 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 2.63 (s, 3H); LC method (A) R t = 7.467 minutes.

[0294] [ka]

[0295] Reagents and conditions: i) BocO, DMAP; ii) tributyl(1-ethoxyvinyl)tin, Pd(PPh)Cl, CsF, CuBr; iii) NBS; iv) (4-formylphenyl)boronic acid, Cu(OAc), TEA; v) 1-methylpiperazine, NaBH(OAc), AcOH; or iv-v) (4-((4-methylpiperazin-1-yl)methyl)phenyl)methanol, DIAD, PPh, THF; vi) SnCl.H0, THF-EtOH; vii) KSCN, AcCl; viii) KCO, MeOH; ix) KCO, EtOH; ix) TFA.

[0296] 4-(4-Aminopyrimidin-2-yl)-N-(2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)phenoxy)phenyl)thiazol-2-amine and benzyloxyphenyl analogs were prepared in 10 steps by a convergent synthesis from commercially available 4-amino-2-chloropyrimidine and 4-methyl-3-nitrophenol (Scheme 4). 4-Amino-2-chloropyrimidine was protected using BocO to give the corresponding bis-carbamate. Stille cross-coupling reaction with tributyl(1-ethoxyvinyl)tin gave the enol ether, which was then transformed into the corresponding α-bromoketone using N-bromosuccinimide. Starting from 4-methyl-3-nitrophenol, O-arylation with (4-formylphenyl)boronic acid under Chan-Lam coupling conditions allowed for the construction of the diphenyl ether moiety, while Mistunobu reaction with the appropriate arylmethanol afforded the corresponding benzyloxyphenyl derivative. Reductive amination afforded the corresponding amine, while reduction of the nitro group, followed by condensation with acetyl isothiocyanate and saponification, afforded the corresponding thiourea. The thiourea was then used with α-bromoketones in the Hantzsch thiazole synthesis to give the corresponding thiazole. Finally, deprotection with TFA gave the expected 4-(4-aminopyrimidin-2-yl)-N-(2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)phenoxy)phenyl)thiazol-2-amine and 4-(4-aminopyrimidin-2-yl)-N-(2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)benzyloxy)phenyl)thiazol-2-amine, respectively.

[0297] 4-(4-aminopyrimidin-2-yl)-N-(2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)phenoxy)phenyl)thiazol-2-amine OR0143 As previously described for N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-aryl)benzamide derivatives (62%) as white powders.1 H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 5.7 Hz, 1H), 7.56 (s, 1H), 7.29 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 2.4 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H), 6.98 (d, J = 8.5 Hz, 2H), 6.70 (dd, J = 8.3, 2.4 Hz, 1H), 6.32 (d, J = 5.7 Hz, 1H), 4.98 (brs, 2H), 3.48 (s, 2H), 2.47 (brs, 8H), 2.28 (s, 3H), 2.26 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 165.76, 163.07, 160.44, 156.67, 156.47, 156.14, 150.46, 139.61, 133.30, 132.05, 130.67, 123.45, LC method (C) R t = 3.476 minutes.

[0298] 4-(4-aminopyrimidin-2-yl)-N-(2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)benzyloxy)phenyl)thiazol-2-amine OR0232 N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-aryl)benzamide derivatives (70%) as white powders as previously described. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 5.7 Hz, 1H), 7.56 (s, 1H), 7.37 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 2.5 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 6.69 (dd, J = 8.3, 2.5 Hz, 1H), 6.32 (d, J = 5.7 Hz, 1H), 5.04 (s, 2H), 5.00 (brs, 2H), 3.51 (s, 2H), 2.46 (brs, 8H), 2.28 (s, 3H), 2.22 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 13C NMR (100 MHz, CDCl3) δ 166.07, 163.09, 160.50, 158.10, 156.47, 150.47, 139.35, 138.16, 135.72, 131.82, 129.52, 127.55, 121.33, 111.08, 110.84, 106.67, 103.39, 70.19. t = 3.679 minutes.

[0299] Di-tert-butyl (2-(2-((2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)phenoxy)phenyl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0143-1 Di-tert-butyl (2-(2-((3-nitroaryl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate derivative (48%) as a light brown powder as previously described. 1H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 5.7 Hz, 1H), 7.52 (d, J = 5.7 Hz, 1H), 7.49 (s, 1H), 7.36 (brs, 1H), 7.28 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 6.97 (d, J = 8.6 Hz, 2H), 6.70 (dd, J = 8.3, 2.4 Hz, 1H), 3.49 (s, 2H), 2.49 (brs, 8H), 2.31 (s, 3H), 2.27 (s, 3H), 1.55 (s, 18H).

[0300] Di-tert-butyl (2-(2-((2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)benzyloxy)phenyl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate OR0232-1 As previously described for the di-tert-butyl (2-(2-((3-nitroaryl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate derivative (76%) as a light brown powder. 1 H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 5.7 Hz, 1H), 7.53 (d, J = 5.7 Hz, 1H), 7.50 (s, 1H), 7.38 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 2.5 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 6.69 (dd, J = 8.3, 2.5 Hz, 1H), 5.04 (s, 2H), 3.51 (s, 2H), 2.47 (brs, 8H), 2.29 (s, 3H), 2.23 (s, 3H), 1.56 (s, 18H).

[0301] 1-(2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)phenoxy)phenyl)thiourea OR0143-2 As previously described for 1-(3-nitroaryl)thiourea derivatives (56%) as white powders. 1 H NMR (400 MHz, CDCl3) δ 7.63 (brs, 1H), 7.30 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 8.3 Hz, 1H), 6.93 (d, J = 8.6 Hz, 2H), 6.92 (dd, J = 8.3, 2.4 Hz, 1H), 6.84 (d, J = 2.4 Hz, 1H), 5.94 (brs, 2H), 3.50 (s, 2H), 2.48 (brs, 8H), 2.29 (s, 3H), 2.27 (s, 3H).

[0302] 1-(2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)benzyloxy)phenyl)thiourea OR0232-2 As previously described for 1-(3-nitroaryl)thiourea derivatives (70%) as white powders. 1 H NMR (400 MHz, MeOD) δ 7.40 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 8.5 Hz, 1H), 6.90 (dd, J = 8.5, 2.5 Hz, 1H), 6.85 (d, J = 2.5 Hz, 1H), 5.06 (s, 2H), 3.54 (s, 2H), 2.50 (brs, 8H), 2.28 (s, 3H), 2.19 (s, 3H).

[0303] N-((2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)phenoxy)phenyl)carbamothioyl)acetamide OR0143-3 The N-((3-nitroaryl)carbamothioyl)acetamide derivative was used in the next step without further purification as previously described.

[0304] N-((2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)benzyloxy)phenyl)carbamothioyl)acetamide OR0232-3 The N-((3-nitroaryl)carbamothioyl)acetamide derivative was used in the next step without further purification as previously described.

[0305] 2-Methyl-5-(4-((4-methylpiperazin-1-yl)methyl)phenoxy)aniline OR0143-4 Di-tert-butyl (2-(2-((3-aminoaryl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate (70%) as previously described as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 8.6 Hz, 2H), 6.97 (d, J = 8.5 Hz, 1H), 6.93 (d, J = 8.6 Hz, 2H), 6.36 (dd, J = 8.5, 2.4 Hz, 1H), 6.33 (d, J = 2.4 Hz, 1H), 3.62 (brs, 2H), 3.47 (s, 2H), 2.46 (brs, 8H), 2.29 (s, 3H), 2.13 (s, 3H).

[0306] 2-Methyl-5-(4-((4-methylpiperazin-1-yl)methyl)benzyloxy)aniline OR0232-4 Di-tert-butyl (2-(2-((3-aminoaryl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate derivative (77%) as previously described as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 6.93 (d, J = 8.5 Hz, 1H), 6.35 (dd, J =8.5, 2.5 Hz, 1H), 6.33 (d, J = 2.5 Hz, 1H), 4.98 (s, 2H), 3.59 (brs, 2H), 3.50 (s, 2H), 2.46 (brs, 8H), 2.29 (s, 3H), 2.10 (s, 3H).

[0307] 1-Methyl-4-(4-(4-methyl-3-nitrophenoxy)benzyl)piperazine OR0143-5 As previously described for the (4-((3-nitroaryl)ethynyl)aryl)methanamine derivative (84%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 2.6 Hz, 1H), 7.32 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 8.4 Hz, 1H), 7.15 (dd, J = 8.4, 2.6 Hz, 1H), 6.97 (d, J = 8.6 Hz, 2H), 3.50 (s, 2H), 2.55 (s, 3H), 2.48 (brs, 8H), 2.30 (s, 3H).

[0308] 1-Methyl-4-(4-((4-methyl-3-nitrophenoxy)methyl)benzyl)piperazine OR0232-5 Under argon, to a solution of 4-methyl-3-nitrophenol (230 mg, 1.5 mmol), (4-((4-methylpiperazin-1-yl)methyl)phenyl)methanol (300 mg, 1.36 mmol), and triphenylphosphine (536 mg, 2.04 mmol) in tetrahydrofuran (68 mL) at 0 °C was added dropwise a solution of diisopropyl azodicarboxylate (430 μL, 2.04 mmol) in tetrahydrofuran (35 mL). The resulting mixture was warmed to room temperature and stirred overnight. The solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography, eluent DCM-MeOH-NHOH (99:1:0.1) to give 1-methyl-4-(4-((4-methyl-3-nitrophenoxy)methyl)benzyl)piperazine OR0232-5 (368 g, 76%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 2.7 Hz, 1H), 7.38-7.34 (m, 4H), 7.23 (d, J = 8.5 Hz, 1H), 7.12 (dd, J = 8.5, 2.7 Hz, 1H), 5.07 (s, 2H), 3.52 (s, 2H), 2.53 (s, 3H), 2.47 (brs, 8H), 2.29 (s, 3H).

[0309] 4-(4-methyl-3-nitrophenoxy)benzaldehyde OR0143-6 To a solution of 4-methyl-3-nitrophenol (1 g, 6.5 mmol), (4-formylphenyl)boronic acid (1.96 g, 13.0 mmol), and copper(II) acetate (1.19 g, 6.5 mmol) in dichloromethane (65 mL) was placed activated molecular sieves and triethylamine (4.6 mL, 35 mmol) was added. The reaction mixture was vigorously stirred under air until complete conversion was monitored by LCMS. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography to give 4-(4-methyl-3-nitrophenoxy)benzaldehyde OR0143-6 (0.57 g, 34%) as a pale yellow powder. 1H NMR (400 MHz, CDCl3) δ 9.96 (s, 1H), 7.90 (d, J = 8.6 Hz, 2H), 7.70 (d, J = 2.5 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.25 (dd, J = 8.4, 2.5 Hz, 1H), 7.11 (d, J = 8.6 Hz, 2H), 2.61 (s, 3H); LCMS C 14 H 11 NO4 method (A) R t = 6.953 min, ESI+ m / z = 258.1 (M+H).

[0310] [ka]

[0311] Reagents and conditions: i) methyl 4-((4-methylpiperazin-1-yl)methyl)benzoate, MeAl, toluene-THF; (ii) Zn, AcOH, EtOAc; iii) AcCl, KSCN, acetone; iv) KCO, MeOH; v) ethyl bromopyruvate, EtOH; vi) malonimidamide dihydrochloride, MeONa, MeOH.

[0312] Condensation of commercially available 4-methyl-3-nitroaniline and methyl 4-((4-methylpiperazin-1-yl)methyl)benzoate in the presence of trimethylaluminum afforded the corresponding amide quantitatively. After reduction of the nitro group, the amine was subjected to acetyl isothiocyanate, followed by saponification to afford the corresponding thiourea. Ethyl bromopyruvate was used with the thiourea in the Hantzsch thiazole synthesis to afford the corresponding thiazole. Finally, tandem addition / cyclization with malonimidamide afforded the expected N-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide dCKi-2.

[0313] N-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide dCKi-2 To a suspension of ethyl 2-((2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)benzamido)phenyl)amino)thiazole-4-carboxylate dCKi-2-1 (2.4 g, 4.8 mmol), malonimidamide dihydrochloride (2.5 g, 14.4 mmol) in methanol (50 mL) was added a 25 wt.% solution of sodium methoxide in MeOH (14.9 mL, 65.2 mmol). The reaction mixture was heated at 70 °C for 2 h and concentrated in vacuo. The crude product was triturated with THF (3 × 50 mL) and the combined organic layers were dried over NaSO. The solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography, gradient DCM-MeOH-NH4OH (100:0:0 to 90:9:1) to give N-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide dCKi-2 (940 mg, 37%) as a light brown powder. Rf=0.10 (DCM-MeOH-NH4OH, 92:7:1); 1 H NMR (300 MHz, DMSO-d6) δ 10.22 (brs, 1H), 9.37 (brs, 1H), 8.84 (d, J = 1.7 Hz, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.51 (dd, J = 8.3, 1.7 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.31 (s, 1H), 7.20 (d, J = 8.3 Hz, 1H), 6.10 (brs, 4H), 5.34 (s, 1H), 3.52 (s, 2H), 2.48-2.30 (m, 8H), 2.22 (s, 3H), 2.19 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 165.56, 165.27, 163.66, 159.29, 151.32, 142.01, 139.60, 137.78, 133.60, 130.66, 128.59, 127.59, 125.97, 116.39, 114.39, 109.48, 81.27, 61.45, 54.46, 52.23, 45.38, 17.41; LCMS C 27 H 31 N9OS method (A) R t = 6.085 min, ESI+ m / z = 530.2 (M+H).

[0314] Ethyl 2-((2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)benzamido)phenyl)amino)thiazole-4-carboxylate dCKi-2-1 To a stirred solution of dCKi-2-2 (4.0 g, 10.0 mmol) in ethanol (100 mL) was added ethyl bromopyruvate (1.5 mL, 12.0 mmol). The resulting mixture was refluxed for 3 hours and then concentrated under reduced pressure. The residue was purified by flash chromatography, gradient DCM-MeOH (100:0 to 80:20) to afford ethyl 2-((2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)benzamido)phenyl)amino)thiazole-4-carboxylate dCKi-2-1 (4.2 g, 85%) as a light brown solid. Rf=0.32 (DCM-MeOH, 9:1); 1H NMR (250 MHz, MeOD) δ 8.21 (d, J = 2.1 Hz, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.64 (s, 1H), 7.58 (dd, J = 8.3, 2.1 Hz, 1H), 7.51 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.3 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.72 (s, 2H), 2.47-3.10 (m, 4H), 2.97-2.60 (m, 4H), 2.84 (s, 3H), 2.30 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H); 13 C NMR (63 MHz, MeOD) δ 168.32, 168.21, 163.33, 163.33, 143.77, 142.36, 140.26, 138.70, 135.52, 132.06, 130.31, 128.87, 127.00, 119.17, 118.19, 115.40, 62.29, 62.19, 54.92, 51.12, 50.02, 49.68, 49.34, 49.00, 48.66, 48.32, 47.98, 43.74, 17.60, 14.58; LCMS C 26 H 31 N5O3S method (A) R t = 6.325 min, ESI+ m / z = 494.0 (M+H).

[0315] N-[3-(carbamothioylamino)-4-methyl-phenyl]-4-[(4-methylpiperazin-1-yl)methyl]benzamide dCKi-2-2 This was used directly in the next step without further purification as a light brown solid, as previously described for the synthesis of 1-(3-nitroaryl)thiourea derivatives (94%): Rf=0.04 (DCM-MeOH 90:10); 1H NMR (250 MHz, DMSO-d6) δ 10.17 (brs, 1H), 9.32 (brs, 1H), 7.89 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 2.0 Hz, 1H), 7.62 (dd, J = 8.3, 2.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.3 Hz, 1H), 3.52 (s, 2H), 2.35 (brs, 8H), 2.14 (s, 6H); 13 C NMR (63 MHz, DMSO-d6) δ 181.46, 165.27, 142.23, 137.59, 137.00, 133.61, 130.43, 129.65, 128.65, 127.58, 119.25, 118.54, 61.62, 54.72, 52.60, 45.76, 17.13; LCMS C 21 H 27 N5OS method (A) R t = 6.259 min, ESI+ m / z = 398.0 (M+H).

[0316] N-[3-(acetylcarbamothioylamino)-4-methyl-phenyl]-4-[(4-methylpiperazin-1-yl)methyl]benzamide dCKi-2-3 This was used directly in the next step without further purification as a light brown solid, as previously described for the synthesis of the N-((3-nitroaryl)carbamothioyl)acetamide derivative (59%). Rf=0.12 (DCM-MeOH 90:10); 1H NMR (250 MHz, DMSO-d6) δ 12.13 (brs, 1H), 11.52 (brs, 1H), 10.27 (brs, 1H), 7.99 (d, J = 1.7 Hz, 1H), 7.94 (d, J = 8.2 Hz, 2H), 7.62 (dd, J = 8.1, 1.7 Hz, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.1 Hz, 1H), 3.65 (s, 2H), 3.40 (brs, 4H), 3.10 (brs, 4H), 2.70 (s, 3H), 2.17 (s, 6H); 13 C NMR (63 MHz, DMSO-d6) δ 179.75, 172.77, 165.15, 140.92, 137.30, 136.65, 133.84, 130.30, 128.87, 128.63, 127.74, 119.11, 118.48, 60.39, 52.75, 49.41, 42.35, 23.79, 17.13; LCMS C 23 H 29 N5O2S method (A) R t = 6.074 min, ESI+ m / z = 440.0 (M+H).

[0317] N-(3-amino-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide dCKi-2-4 To a solution of dCKi-2-5 (9.3 g, 25.3 mmol) in a mixture of ethyl acetate and acetic acid (2:1, 300 mL) was carefully added zinc powder (24.4 g, 25.3 mmol). The resulting mixture was stirred at room temperature for 3 h, then filtered through a Celite pad and washed with EtOAc (200 mL). The filtrate was concentrated under reduced pressure, and the crude residue was subsequently dissolved in water, followed by the addition of Na2CO3 until pH = 9 and extraction with EtOAc. The combined organic layers were dried over Na2SO4, and the solvent was evaporated under reduced pressure to give N-(3-amino-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide dCKi-2-4 (8.5 g, quantitative) as a light brown solid, which was used in the next step without further purification. Rf = 0.11 (DCM-MeOH-NH4OH 92:7:1); 1 H NMR (250 MHz, DMSO-d6, δ) 9.86 (brs, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 1.4 Hz, 1H), 6.91-6.73 (m, LCMS C 20 H 26 N4O method (A) R t = 4.346 min, ESI+ m / z = 339.0 (M+H).

[0318] N-(4-methyl-3-nitrophenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide dCKi-2-5 To a stirred solution of a mixture of 4-methyl-3-nitroaniline (4.2 g, 27.6 mmol) and methyl 4-((4-methylpiperazin-1-yl)methyl)benzoate (6.3 g, 25.3 mmol) in toluene-tetrahydrofuran (3:1, 320 mL) under argon at 0° C. was added dropwise a 2 M solution of trimethylaluminum in toluene (40 mL, 80 mmol). The resulting mixture was warmed to room temperature and heated to 50°C for 6 hours. The mixture was carefully poured onto ice (200 g) and quenched by adding 10% aqueous NaOH (150 mL). After stirring for 30 minutes, the aqueous phase was extracted with DCM (3 x 200 mL). The combined organic layers were concentrated to dryness under reduced pressure to give N-(4-methyl-3-nitrophenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide dCKi-2-5 (9.3 g, quantitative) as a light brown solid, which was used in the next step without further purification. Rf = 0.27 (DCM-MeOH-NH4OH 92:7:1); 1 H NMR (250 MHz, CDCl3) δ 8.25 (d, J = 2.3 Hz, 1H), 8.04 (brs, 1H), 7.91 (dd, J = 8.3, 2.3 Hz, 2H), 7.83 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.3 Hz, 1H), 3.58 (s, 2H), 2.59 (s, 3H), 2.70-2.25 (m, 8H), 2.30 (s, 3H); 13 C NMR (63 MHz, CDCl3) δ 166.03, 149.07, 143.32, 137.06, 133.33, 132.91, 129.49, 129.33, 127.25, 124.93, 116.28, 62.56, 55.18, 53.22, 46.14, 20.13; LCMS C 20 H 24 N4O3 method (A) R t = 6.479 min, ESI+ m / z = 369.0 (M+H).

[0319] [ka]

[0320] Reagents and conditions: i) ArB(OR)2, PdCl2(dppf), Na2CO3; ii) H2, Pd / C, THF-EtOH; iii) RCHO, NaBH(OAc)3, AcOH, THF; iv) PhCONCS, acetone v) K2CO3, MeOH; vi) ethyl bromopyruvate, THF; vii) malonimidamide dihydrochloride, MeONa, MeOH.

[0321] N-([1,1'-biaryl]-3-yl)-4-(4,6-diaminopyrimidin-2-yl)thiazol-2-amine derivatives were prepared in seven steps (Scheme 6). Starting from the appropriate bromo-3-nitrobenzene, Suzuki cross-coupling reactions with arylboronic acid derivatives allowed the introduction of key biphenyl scaffolds. Reduction of the nitro group, followed by sequential alkylation, followed by condensation with benzoyl isothiocyanate and saponification afforded the corresponding thioureas. Ethyl bromopyruvate was used with the thioureas in the Hantzsch thiazole synthesis to afford the corresponding thiazoles. Finally, tandem addition / cyclization with malonimidamide afforded the expected structurally diverse N-([1,1'-biaryl]-3-yl)-4-(4,6-diaminopyrimidin-2-yl)thiazol-2-amines.

[0322] [ka]

[0323] Reagents and conditions: i) RYCZ; ii) optionally K2CO3, MeOH; iii) ethyl bromopyruvate, THF; iv) R3Br, Cs2CO3, DMF; v) malonimidamide dihydrochloride, MeONa, MeOH; vi) appropriate ArB(OR)2 or ArX, PdCl2(dppf), Na2CO3; vii) (PinB)2, PdCl2(dppf), KOAc.

[0324] Alternatively, N-([1,1'-biaryl]-3-yl)-4-(4,6-diaminopyrimidin-2-yl)thiazol-2-amine derivatives and analogs were prepared from commercially available aminohalogenobenzenes (Scheme 7) via a convergent approach. For example, starting from 5-bromo- or 5-iodo-2-methylaniline, condensation with benzoyl isothiocyanate and saponification afforded the corresponding thiourea. Ethyl bromopyruvate was used with the thiourea in the Hantzsch thiazole synthesis to give the corresponding thiazole. The thiazole derivative was then transformed into the expected N-([1,1'-biaryl]-3-yl)-4-(4,6-diaminopyrimidin-2-yl)thiazol-2-amine by Suzuki cross-coupling via an aryl boronate or halogenoaryl precursor.

[0325] General procedure for the synthesis of 2-[2-(biaryl-3-ylamino)-thiazol-4-yl]-pyrimidine-4,6-diamine hydrochloride. To a solution of the appropriate mixture of 2-[2-(biaryl-3-ylamino)-thiazol-4-yl]-pyrimidine-4,6-diamine (1.5 mmol) in methanol-dichloromethane (5:2, 35 mL) was added dropwise a 1N solution of hydrogen chloride in diethyl ether (3.2 mL, 3.2 mmol). The resulting solution was stirred at room temperature for 30 minutes and concentrated under reduced pressure to almost no volume. The residue was crystallized from EtO with vigorous stirring to give the expected 2-[2-(biaryl-3-ylamino)-thiazol-4-yl]-pyrimidine-4,6-diamine hydrochloride.

[0326] 2-(2-((4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-2'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine hydrochloride OR0642 (93%) as a pale yellow powder. 11H NMR (400 MHz, MeOD) δ 8.17 (s, 1H), 8.15 (dd, J = 8.1, 1.7 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.69 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.41 (dd, J = 7.9, 1.6 Hz, 1H), 7.34 (s, 1H), 5.67 (s, 1H), 4.28 (brs, 1H), 4.01 (brs, 2H), 3.85 (brs, 1H), 3.61 (brs, 2H), 3.30 (brs, 2H), 2.93 (brs, 2H), 2.92 (s, 3H), 2.34 (s, 3H), 1.72 (sextet, J = 7.4 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H). 13 13C NMR (100 MHz, MeOD) δ 172.73, 152.34, 146.43, 144.00, 143.15, 139.26, 138.98, 136.95, 135.12, 133.51, 132.38, 130.94, 130.62, 126.74, 126.04, 123.32, 115.99, 80.46, 54.70, 53.95, 44.53, 43.49, 22.09, 17.51, 11.75.

[0327] General procedure for the synthesis of 2-[2-(biaryl-3-ylamino)-thiazol-4-yl]-pyrimidine-4,6-diamine and analogs. Method (A): Briefly, as previously described for the synthesis of dCKi-2, to a suspension of ethyl 2-([1,1'-aryl]-3-yl-amino)thiazole-4-carboxylate derivative or analog (0.76 mmol), malonimidamide dihydrochloride (225 mg, 1.28 mmol) in methanol (8 mL) was added a 25 wt.% solution of sodium methoxide in MeOH (1.56 mL, 6.80 mmol). The reaction mixture was heated at 70 °C for 4 h and concentrated in vacuo. The crude product was triturated with THF (3 × 50 mL), and the combined organic layers were dried over Na SO . The solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography to give the corresponding 2-[2-(biaryl-3-ylamino)-thiazol-4-yl]-pyrimidine-4,6-diamine or analog. Method (B): Under argon, a suspension of the appropriate 2-(2-(5-halogenophenyl)(amino)thiazol-4-yl)pyrimidine-4,6-diamine (0.214 mmol), aryl boronate or aryl boronic acid (0.286 mmol), PdCl(dppf) (21 mg, 0.028 mmol), and KCO (103 mg, 0.745 mmol) in a degassed 1,4-dioxane-water mixture (5:1, 12 mL) was heated at 80 °C for 1.5 h, after which the starting material was completely consumed. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography to give the corresponding 2-[2-(biaryl-3-ylamino)-thiazol-4-yl]-pyrimidine-4,6-diamine. Method (C): As previously described for the synthesis of N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-aryl)benzamide derivatives from the appropriate tert-butyl (biaryl-3-yl-[4-(4,6-diamino-pyrimidin-2-yl)-thiazol-2-yl]-aminoalkyl)carbamate.

[0328] 2-(2-((4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0600 (Method A, 25%) as a light brown solid. Rf=0.25 (DCM-MeOH-NH4OH, 90:9:1); 1 H NMR (400 MHz, CDCl3) δ 7.52 (dd, J = 8.2, 2.0 Hz, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.31 (s, 1H), 7.27 (d, J = 8.4 Hz, 2H), 5.42 (s, 1H), 4.71 (brs, 4H), 4.01 (brs, 2H), 2.86-2.81 (m, 2H), 2.66-2.61 (m, 2H), 2.50 (brs, 8H), 2.30 (s, 3H), 2.26 (s, 3H), 1.66 (sextet, J = 7.4 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 171.22, 163.93, 160.87, 151.29, 143.34, 140.77, 139.91, 137.91, 136.29, 132.50, 129.38, 128.02, 127.00, 126.96, 110.80, 83.01, 60.52, 55.27, 53.62, 53.30, 46.20, 33.35, 21.33, 17.49, 11.42; 30 H 38 N8S method (B) R t = 4.243 min, ESI+ m / z = 543.3 (M+H).

[0329] 2-(2-((4-methyl-4'-(3-(4-methylpiperazin-1-yl)propyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0601 (Method A, 40%) as a pale yellow solid. Rf=0.25 (DCM-MeOH-NH4OH, 90:9:1); 1 H NMR (400 MHz, CDCl3) δ 7.52 (dd, J = 8.0, 1.8 Hz, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 1.8 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.31 (s, 1H), 7.25 (d, J = 8.1 Hz, 2H), 5.42 (s, 1H), 4.82 (brs, 4H), 4.01 (brs, 2H), 2.66 (t, J = 7.7 Hz, 2H), 2.51 (brs, 8H), 2.44-2.38 (m, 2H), 2.31 (s, 3H), 2.25 (s, 3H), 1.85 (quintet, J = 7.7 Hz, 2H), 1.66 (sextet, J = 7.5 Hz, , 2H), 0.92 (t, J = 7.5 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 171.19, 163.80, 160.57, 151.07, 143.31, 141.64, 140.80, 137.61, 136.18, 132.48, 129.06, 127.93, LCMS C 31 H 40 N8S method (B) R t = 4.279 min, ESI+ m / z = 557.3 (M+H).

[0330] 2-(2-((2-methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0602 (Method A, 34%) as a white powder. Rf=0.25 (DCM-MeOH-NH4OH, 90:9:1); 1 H NMR (400 MHz, CDCl3) δ 8.74 (d, J = 2.0 Hz, 1H), 7.77 (dd, J = 8.1, 2.0 Hz, 1H), 7.51 (dd, J = 7.9, 1.8 Hz, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.32 (s, 1H), 7.25 (d, J = 8.1 Hz, 1H), 5.44 (s, 1H), 4.71 (brs, 4H), 4.01 (brs, 2H), 3.05-3.00 (m, 2H), 2.82-2.77 (m, 2H), 2.60 (brs, 4H), 2.48 (brs, 4H), 2.29 (s, 3H), 2.28 (s, 3H), 1.66 (sextet, J = 7.4 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 171.00, 163.92, 160.82, 159.60, 151.33, 147.56, 143.64, 137.64, 137.33, 134.71, 133.18, 132.87, LCMS C 29 H 37 N9S method (B) R t = 3.952 min, ESI+ m / z = 544.3 (M+H).

[0331] 2-(2-(isobutyl(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0603 (Method A, 23%) as a light brown powder. Rf=0.5 (DCM-MeOH-NH4OH, 90:9:1); 1 H NMR (400 MHz, CDCl3) δ 7.52 (dd, J = 7.6, 1.9 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 7.6 Hz, 1H), 7.32 (s, 1H), 7.28 (d, J = 8.2 Hz, 2H), 5.41 (s, 1H), 4.70 (brs, 4H), 3.84 (brs, 2H), 2.88-2.80 (m, 2H), 2.67-2.61 (m, 2H), 2.56 (brs, 8H), 2.30 (s, 3H), 2.26 (s, 3H), 2.04 (septet, J = 6.8 Hz, 1H), 1.00 (d, J = 6.8 Hz, 6H). 13 C NMR (100 MHz, CDCl3) δ 171.69, 163.92, 160.89, 151.35, 144.07, 140.59, 139.89, 138.00, 135.94, 132.71, 129.39, 127.87, LCMS C 31 H 40 N8S method (B) R t = 4.368 min, ESI+ m / z = 557.2 (M+H).

[0332] 2-(2-((cyclopropylmethyl)(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0604 (Method A, 8%) as a light brown powder. Rf=0.5 (DCM-MeOH-NH4OH, 90:9:1); 1 H NMR (400 MHz, CDCl3) δ 7.53 (dd, J = 8.7, 1.9 Hz, 1H), 7.52 (d, J = 1.9 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.7 Hz, 1H), 7.31 (s, 1H), 7.28 (d, J = 8.2 Hz, 2H), 5.44 (s, 1H), 4.68 (brs, 4H), 3.96 (brs, 2H), 2.89-2.80 (m, 2H), 2.68-2.60 (m, 2H), 2.53 (brs, 8H), 2.32 (s, 3H), 2.29 (s, 3H), 1.17-1.05 (m, 1H), 0.44-0.37 (m, 2H), 0.19-0.11 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 171.25, 163.90, 160.90, 151.20, 143.55, 140.63, 139.80, 138.01, 136.48, 132.27, 129.37, 128.44, 126.97, 110.95, 83.01, 60.48, 56.51, 55.21, 53.19, 46.12, 33.32, 17.48, 9.88, 3.97; LCMS C 31 H 38 N8S method (B) R t = 4.235 min, ESI+ m / z = 555.3 (M+H).

[0333] 2-(2-(isopentyl(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0605 (Method A, 28%) as a pale yellow solid. Rf=0.5 (DCM-MeOH-NH4OH, 90:9:1); 1 H NMR (400 MHz, CDCl3) δ 7.52 (dd, J = 7.9, 1.8 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 1.8 Hz, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.33 (s, 1H), 7.27 (d, J = 8.2 Hz, 2H), 5.45 (s, 1H), 4.85 (brs, 4H), 4.07 (brs, 2H), 2.90-2.82 (m, 2H), 2.73-2.66 (m, 2H), 2.65 (brs, 8H), 2.39 (s, 3H), 2.25 (s, 3H), 1.71-1.59 (m, 1H), 1.50 (q, J = 7.3 Hz, 2H), 0.90 (d, J = 6.6 Hz, 6H); 13 C NMR (100 MHz, CDCl3) δ 171.26, 163.56, 143.30, 140.69, 139.52, 138.03, 136.34, 132.51, 129.38, 127.90, 127.05, 126.97, 111.15, 82.88, 60.12, 54.82, 52.55, 50.66, 45.67, 36.64, 33.12, 26.43, 22.83, 17.54; LCMS C 32 H 40 N8S method (B) R t = 4.452 min, ESI+ m / z = 571.4 (M+H).

[0334] 2-(2-(butyl(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0606 (Method A, 19%) as a light brown solid. Rf=0.5 (DCM-MeOH-NH4OH, 90:9:1); 1 H NMR (400 MHz, CDCl3) δ 7.53 (dd, J = 8.0, 1.7 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 1.7 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.32 (s, 1H), 7.27 (d, J = 8.2 Hz, 2H), 5.45 (s, 1H), 4.82 (brs, 4H), 4.05 (brs, 2H), 2.87-2.83 (m, 2H), 2.69-2.65 (m, 2H), 2.57 (brs, 8H), 2.37 (s, 3H), 2.25 (s, 3H), 1.60-1.58 (m, 2H), 1.38-1.35 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 171.28, 163.65, 150.79, 143.30, 140.73, 139.64, 137.99, 136.32, 132.52, 129.38, 127.98, 127.03, LCMS C 31 H 40 N8S method (B) R t = 4.394 min, ESI+ m / z = 557.3 (M+H).

[0335] 2-(2-((4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0607 (Method B, 76%) as a light brown solid. Rf=0.45 (DCM-MeOH-NH4OH, 90:9:1); 1 H NMR (400 MHz, MeOD) δ 7.89 (d, J = 8.7 Hz, 2H), 7.85 (d, J = 8.7 Hz, 2H), 7.71 (dd, J = 8.0, 1.8 Hz, 1H), 7.66 (d, J = 1.8 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.25 (s, 1H), 5.54 (s, 1H), 4.01 (brs, 2H), 3.08-3.04 (m, 4H), 2.53-2.49 (m, 4H), 2.31 (s, 3H), 2.26 (s, 3H), 1.74 (sextet, J = 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, MeOD) δ 171.99, 165.62, 161.25, 152.08, 145.86, 145.04, 140.31, 139.04, 135.59, 134.14, 129.71, 129.44, 128.58, 128.51, 111.01, 82.96, 55.09, 54.87, 46.95, 45.75, 22.31, 17.61, 11.61; LCMS C 28 H 34 N8O2S2 method (B) R t = 4.496 min, ESI+ m / z = 579.3 (M+H).

[0336] 2-(2-(isobutyl(2-methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-3-yl)phenyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0608 (Method A, 9%) as a pale yellow solid. Rf=0.5 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 2.5 Hz, 1H), 7.77 (dd, J = 8.6, 2.5 Hz, 1H), 7.46 (dd, J = 7.8, 1.7 Hz, 1H), 7.43 (d, J = 1.7 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.35 (s, 1H), 6.83 (d, J = 8.6 Hz, 1H), 5.50 (s, 1H), 5.04 (brs, 4H), 4.49 (t, J = 5.7 Hz, 2H), 3.80 (brs, 2H), 2.87 (t, J = 5.7 Hz, 2H), 2.80-2.60 (m, 8H), 2.43 (s, 3H), 2.26 (s, 3H), 2.10-1.96 (m, 1H), 1.00 (d, J = 6.6 Hz, 6H). 13 C NMR (100 MHz, CDCl3) δ 171.42, 163.70, 163.30, 160.26, 151.03, 144.88, 144.16, 137.42, 137.33, 136.17, 132.96, 129.13, LCMS C 30 H 39 N9OS method (B) R t = 5.303 min, ESI+ m / z = 574.3 (M+H).

[0337] N-((1-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(isobutyl)amino)-4-methylphenyl)-1H-1,2,3-triazol-4-yl)methyl)methanesulfonamide OR0609 (Method A, 18%) as a light brown powder. Rf=0.5 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, MeOD) δ 8.51 (s, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.82 (dd, J = 8.3, 2.2 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.30 (s, 1H), 5.53 (s, 1H), 4.45 (s, 2H), 3.91 (brs, 2H), 2.99 (s, 3H), 2.33 (s, 3H), 2.08-1.96 (m, 1H), 1.03 (d, J = 6.7 Hz, 6H); 13 C NMR (100 MHz, MeOD) δ 172.12, 165.62, 161.25, 152.19, 147.17, 145.86, 139.43, 137.65, 134.79, 122.65, 122.30, 121.25, 111.43, 83.02, 60.94, 40.62, 39.00, 28.74, 20.78, 17.85; LCMS C 22 H 28 N 10 O2S2 method (B) R t = 4.585 min, ESI+ m / z = 529.2 (M+H).

[0338] 2-(2-((2-aminoethyl)(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0610 (Method C, 74%) as a pale yellow solid. Rf=0.40 (DCM-MeOH-NH4OH, 80:18:2); 1H NMR (400 MHz, CDCl3) δ 7.49-7.47 (m, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.5 Hz, 1H), 7.25 (s, 1H), 7.20 (d, J = 8.1 Hz, 2H), 5.71 (brs, 4H), 4.16 (brs, 1H), 3.80 (brs, 1H), 3.48-3.20 (m, 2H), 2.79-2.75 (m, 2H), 2.59-2.56 (m, 2H), 2.48 (brs, 8H), 2.33 (s, 3H), 2.14 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.65, 163.08, 162.63, 162.29, 143.80, 141.26, 139.88, 137.34, 134.63, 132.79, 129.41, 127.59, LCMS C 29 H 37 N9S method (B) R t = 3.649 min, ESI+ m / z = 544.2 (M+H).

[0339] tert-Butyl (2-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-bi-phenyl]-3-yl)amino)ethyl)carbamate OR0610-1 (Method A, 31%) as a light brown solid. Rf=0.33 (DCM-MeOH-NH4OH, 90:9:1); LCMS C 34 H 45 N9O2S, method (B)R t =4.360 min, ESI+m / z=644.4(M+H).

[0340] 2-(2-((3-aminopropyl)(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0611 (Method C, 50%) as a pale yellow solid. Rf=0.55 (DCM-MeOH-NH4OH, 80:18:2); 1 H NMR (400 MHz, CDCl3) δ 7.47 (dd, J = 8.1, 1.2 Hz, 1H), 7.41 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 1.2 Hz, 1H), 7.21 (d, J = 8.2 Hz, 2H), 7.15 (s, 1H), 5.51 (brs, 4H), 5.29 (s, 1H), 4.15 (brs, 1H), 3.81 (brs, 1H), 3.18-3.16 (m, 2H), 2.84-2.76 (m, 2H), 2.63- 2.53 (m, 2H), 2.47 (brs, 8H), 2.28 (s, 3H), 2.13 (s, 3H), 2.01-1.97 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 171.39, 164.09, 159.70, 150.42, 143.27, 141.36, 140.09, 137.45, 135.13, 132.80, 129.41, 127.47, 127.01, 110.34, 83.57, 60.45, 55.24, 53.56, 53.26, 50.17, 46.18, 33.31, 29.84, 17.44; LCMS C 30 H 39 N9S method (B) R t = 3.671 min, ESI+ m / z = 558.3 ​​(M+H).

[0341] tert-Butyl (3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)propyl)carbamate OR0611-1 (Method A, 39%) as a light brown solid. Rf=0.50 (DCM-MeOH-NH4OH, 90:9:1); LCMS C 35 H 47 N9O2S, method (B)R t =4.450 min, ESI+m / z=658.4(M+H).

[0342] 2-[2-({2-methyl-5-[6-(4-methyl-piperazin-1-ylcarbonyl)-pyridin-3-yl]-phenyl}-propyl-amino)-thiazol-4-yl]-pyrimidine-4,6-diamine OR0612 (Method A, 2%) as a pale yellow solid. Rf=0.5 (DCM-MeOH-NH4OH, 90:9:1); 1 H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 2.0 Hz, 1H), 7.96 (dd, J = 8.1, 2.0 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.54 (dd, J = 7.9, 1.4 Hz, 1H), 7.47 (d, J = 1.4 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.35 (s, 1H), 5.53 (s, 1H), 5.26 (brs, 4H), 3.98 (brs, 2H), 3.87-3.83 (m, 2H), 3.70-3.66 (m, 2H), 2.55-2.51 LCMS C 28 H 33 N9OS method (B) R t = 4.071 min, ESI+ m / z = 544.3 (M+H).

[0343] 2-(2-((5-(2-aminopyrimidin-5-yl)-2-methylphenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0613 (Method B, 67%) as a light brown solid. Rf=0.45 (DCM-MeOH-NH4OH, 95:4.5:0.5); 1 H NMR (400 MHz, MeOD) δ 8.54 (s, 2H), 7.54 (dd, J = 8.0, 1.7 Hz, 1H), 7.50 (d, J = 1.7 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.29 (s, 1H), 5.54 (s, 1H), 3.98 (brs, 2H), 2.27 (s, 3H), 1.72 (sextet, J = 7.5 Hz, 2H), 0.97 (t, J = 7.5 Hz, 3H); 13 C NMR (100 MHz, MeOD) δ 200.27, 193.20, 192.10, 188.30, 185.51, 179.17, 173.11, 165.67, 164.59, 162.29, 155.80, 155.25, 152.22, 139.76, 110.84, 83.11, 50.40, 45.71, 39.78; LCMS C 21 H 23 N9S method (B) R t = 4.620 min, ESI+ m / z = 434.2 (M+H).

[0344] 2-(2-((4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0614 (Method B, 35%) as a pale yellow solid. Rf=0.22 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.2 Hz, 2H), 7.67 (s, 1H), 7.62 (d, J = 8.2 Hz, 2H), 7.40 (s, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 5.39 (s, 1H), 5.13 (brs, 4H), 3.03-2.99 (m, 4H), 2.46-2.42 (m, 4H), 2.21 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ 166.59, 163.71, 159.74, 150.31, 145.04, 139.70, 138.20, 133.70, 131.96, 130.67, 128.45, 127.45, 123.37, 119.60, 110.58, 83.12, 67.13, 58.30, 54.04, 46.02, 45.71, 18.47, 17.66; LCMS C 25 H 28 N8O2S2 method (B) R t = 4.109 min, ESI+ m / z = 537.2 (M+H).

[0345] 3'-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4'-methyl-[1,1'-biphenyl]-4-sulfonamide OR0615 (Method B, 36%) as a light brown solid. Rf=0.27 (DCM-MeOH-NH4OH, 90:9:1); 1 H NMR (400 MHz, MeOD) δ 7.97 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.66 (dd, J = 8.1, 1.8 Hz, 1H), 7.60 (d, J = 1.8 Hz 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.29 (s, 1H), 5.55 (s, 1H), 3.98 (brs, 2H), 2.28 (s, 3H), 1.71 (sextet, J = 7.5 Hz, 2H), 0.97 (t, J = 7.5 Hz, 3H);13 C NMR (100 MHz, MeOD) δ 172.10, 165.00, 160.09, 150.99, 144.82, 144.72, 143.93, 140.59, 138.61, 134.05, 129.19, 128.50, 128.26, 127.88, 111.66, 82.69, 54.91, 22.25, 17.60, 11.63; LCMS C 23 H 25 N7O2S2 method (B) R t = 4.933 min, ESI+ m / z = 496.2 (M+H).

[0346] N-(5-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)pyridin-2-yl)-4-methylpiperazine-1-carboxamide OR0616 (Method A, 19%) as a pale yellow solid. Rf=0.5 (DCM-MeOH-NH4OH, 90:9:1); 1 H NMR (400 MHz, DMSO-d6) δ 9.28 (brs, 1H), 8.59 (d, J = 2.3 Hz, 1H), 8.03 (dd, J = 8.8, 2.3 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.68 (dd, J = 7.9, 1.8 Hz, 1H), 7.67 (d, J = 1.8 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.17 (s, 1H), 6.03 (brs, 4H), 5.34 (s, 1H), 3.89 (brs, 2H), 3.50-3.42 (m, 4H), 2.33-2.26 (m, 4H), 2.21 (s, 3H), 2.18 (s, 3H), 1.62 (sextet, J = 7.4 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H); LCMS C 28 H 34 N 10 OS method (B) R t = 4.237 min, ESI+ m / z = 559.3 (M+H).

[0347] 2-(2-((4-methyl-4'-(morpholinosulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0617 (Method B, 61%) as a pale yellow solid. Rf=0.50 (DCM-MeOH-NH4OH, 90:9:1); 1 H NMR (400 MHz, MeOD) δ 7.90 (d, J = 8.5 Hz, 2H), 7.85 (d, J = 8.5 Hz, 2H), 7.71 (dd, J = 8.0, 1.7 Hz, 1H), 7.67 (d, J = 1.7 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.26 (s, 1H), 5.54 (s, 1H), 4.02 (brs, 2H), 3.73-3.69 (m, 4H), 3.02-2.98 (m, 4H), 2.31 (s, 3H), 1.63 (sextet, J = 7.3 Hz, 2H), 0.99 (t, J = 7.3 Hz, 3H); 13 C NMR (100 MHz, MeOD) δ 172.00, 165.60, 161.21, 152.04, 145.94, 145.04, 140.32, 139.04, 135.37, 134.13, 129.78, 129.46, 128.61, 128.55, 111.03, 82.95, 67.23, 54.90, 47.46, 22.31, 17.62, 11.61; LCMS C 27 H 31 N7O3S2 method (B) R t = 5.538 min, ESI+ m / z = 566.2 (M+H).

[0348] 3'-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-N,N,4'-trimethyl-[1,1'-biphenyl]-4-sulfonamide OR0618 (Method B, 67%) as a light brown solid. Rf=0.55 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, MeOD) δ 7.88 (d, J = 8.7 Hz, 2H), 7.85 (d, J = 8.7 Hz, 2H), 7.71 (dd, J = 7.9, 1.4 Hz, 1H), 7.66 (J = 1.4 Hz, 1H), 7.53 (J = 7.9 Hz, 1H), 7.25 (s, 1H), 5.54 (s, 1H), 4.02 (brs, 2H), 2.71 (s, 6H), 2.31 (s, 3H), 1.74 (sextet, J = 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, MeOD) δ 172.00, 165.57, 161.16, 151.99, 145.63, 145.01, 140.38, 138.95, 135.44, 134.11, 132.26, 129.65, 129.41, 128.51, 111.05, 82.94, 54.88, 38.30, 22.30, 17.61, 11.61; LCMS C 25 H 29 N7O2S2 method (B) R t = 5.395 min, ESI+ m / z = 524.2 (M+H).

[0349] 2-(2-((4'-((dimethylamino)methyl)-4-methyl-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0619 (Method B, 61%) as a pale yellow solid. Rf=0.50 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, MeOD) δ 7.63 (dd, J = 8.0, 1.8 Hz, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 1.8 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.1 Hz, 2H), 7.23 (s, 1H), 5.54 (s, 1H), 4.01 (brs, 2H), 3.51 (s, 2H), 2.28 (s, 3H), 2.26 (s, 6H), 1.73 (sextet, J = 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, MeOD) δ 172.18, 165.64, 161.34, 152.03, 144.75, 141.99, 140.42, 138.13, 137.33, 133.79, 131.38, 128.89, 128.18, 127.75, 110.91, 82.96, 64.53, 54.76, 45.22, 22.30, 17.50, 11.61; LCMS C 26 H 31 N7S method (B) R t = 4.385 min, ESI+ m / z = 474.3 (M+H).

[0350] 2-(2-((2-methyl-5-(pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0620 (Method B, 86%) as a light brown solid. Rf=0.50 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, MeOD) δ 8.81 (d, J = 1.8 Hz, 1H), 8.52 (dd, J = 4.9, 1.8 Hz, 1H), 8.10 (dt, J = 8.0, 1.8 Hz, 1H), 7.67 (dd, J = 7.8, 1.9 Hz, 1H), 7.63 (d, J = 1.9 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.52 (dd, J = 8.0, 4.9 Hz, 1H), 7.25 (s, 1H), 5.54 (s, 1H), 4.01 (brs, 2H), 2.31 (s, 3H), 1.74 (sextet, J = 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, MeOD) δ 171.98, 165.61, 161.25, 152.05, 149.00, 148.19, 145.12, 138.79, 138.49, 137.44, 136.37, 134.21, 129.17, 128.33, 125.57, 111.01, 82.96, 54.92, 22.30, 17.61, 11.60; LCMS C 22 H 23 N7S method (B) R t = 4.544 min, ESI+ m / z = 418.2 (M+H).

[0351] (5-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)pyridin-2-yl)(morpholino)methanone OR0621 (Method B, 71%) as a pale yellow solid. Rf=0.50 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, MeOD) δ 8.88 (d, J = 2.0 Hz, 1H), 8.21 (dd, J = 8.2, 2.0 Hz, 1H), 7.73 (dd, J = 8.0, 1.8 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.25 (s, 1H), 5.53 (s, 1H), 4.02 (brs, 2H), 3.79 (brs, 4H), 3.70-3.64 (m, 2H), 3.62-3.56 (m, 2H), 2.32 (s, 3H), 1.74 (sextet, J = 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, MeOD) δ 171.91, 169.24, 165.61, 161.24, 153.30, 152.08, 147.72, 145.20, 139.29, 138.03, 137.87, 136.88, 134.30, 129.36, 128.41, 124.96, 111.02, 82.97, 67.93, 54.94, 44.00, 22.30, 17.65, 11.60; 27 H 30 N8O2S method (B) R t = 4.835 min, ESI+ m / z = 531.2 (M+H).

[0352] Methyl 5-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)picolinate OR0622 (Method B, 42%) as a light brown solid. Rf=0.50 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, MeOD) δ 8.95 (dd, J = 2.0, 0.6 Hz, 1H), 8.27 (dd, J = 8.2, 2.0 Hz, 1H), 8.22 (dd, J = 8.2, 0.6 Hz, 1H), 7.75 (dd, J = 8.0, 1.8 Hz, 1H), 7.73 (d, J = 1.8 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.26 (s, 1H), 5.54 (s, 1H), 4.02 (brs, 2H), 4.00 (s, 3H) 2.33 (s, 3H), 1.74 (sextet, J = 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H). ; 13 C NMR (100 MHz, MeOD) δ 171.88, 166.44, 165.59, 161.19, 152.06, 148.65, 147.36, 145.28, 140.31, 139.80, 137.46, 136.88, 134.38, 129.52, 128.54, 126.61, 111.07, 82.96, 54.99, 53.24, 22.30, 17.69, 11.60; LCMS C 24 H 25 N7O2S method (B) R t = 5.062 min, ESI+ m / z = 476.3 (M+H).

[0353] N-(5-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)pyridin-2-yl)-4-methylpiperazine-1-sulfonamide OR0625 (Method A, 18%) as a white powder. Rf=0.5 (DCM-MeOH-NH4OH, 90:9:1); 1 H NMR (400 MHz, DMSO-d6) 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 2.0 Hz, 1H), 8.12 (dd, J = 8.8, 2.0 Hz, 1H), 7.71 (dd, J = 8.4, 1.8 Hz, 1H), 7.70 (d, J = 1.8 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.41 (s, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.03 (s, 4H), 5.48 (s, 1H), 3.97 (brs, 2H), 3.25-3.21 (m, 4H), 2.56-2.52 (m, 4H), 2.28 (s, 3H), 2.22 (s, 3H), 1.62 (sextet, J = 7.4 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H); LCMS C 27 H 34 N 10 O2S2 method (B) R t = 4.182 min, ESI+ m / z = 595.3 (M+H).

[0354] 2-(2-((5-(1H-indol-5-yl)-2-methylphenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0626 (Method B, 82%) as a pale yellow solid. Rf=0.50 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, MeOD) δ 7.78 (d, J = 1.8 Hz, 1H), 7.63 (dd, J = 7.9, 1.8 Hz, 1H), 7.53 (d, J = 1.6 Hz, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.36 (dd, J = 8.2, 1.6 Hz, 1H), 7.25 (s, 1H), 7.24 (d, J = 2.8 Hz, 1H), 6.50 (d, J = 2.8 Hz, 1H), 5.54 (s, 1H), 4.00 (brs, 2H), 2.27 (s, 3H), 1.75 (sextet, J = 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, MeOD) δ 172.44, 165.37, 160.86, 151.48, 144.48, 144.22, 137.37, 135.56, 133.49, 132.36, 130.07, 128.85, LCMS C 25 H 25 N7S method (B) R t = 5.452 min, ESI+ m / z = 456.2 (M+H).

[0355] 2-(2-((2-methyl-5-(6-((4-methylpiperazin-1-yl)sulfonyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0627 (Method A, 22% or Method B, 71%) as a pale yellow powder. Rf=0.50 (DCM-MeOH-NH4OH, 90:10:1); 1H NMR (400 MHz, MeOD) δ 9.00 (d, J = 1.8 Hz, 1H), 8.31 (dd, J = 8.2, 1.8 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.76 (dd, J = 7.8, 1.9 Hz, 1H), 7.74 (d, J = 1.9 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.26 (s, 1H), 5.53 (s, 1H), 4.02 (brs, 2H), 3.35-3.30 (m, 4H), 2.54-2.46 (m, 4H), 2.33 (s, 3H), 2.28 (s, 3H), 1.74 (sextet, J = 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, MeOD) δ 171.84, 165.64, 161.29, 155.57, 152.17, 149.29, 145.31, 140.03, 139.92, 137.40, 137.14, 134.41, 129.64, 128.60, 124.55, 111.02, 82.99, 55.38, 55.00, 47.30, 45.87, 22.30, 17.70, 11.60; 27 H 33 N9O2S2 method (B) R t = 4.346 min, ESI+ m / z = 580.3 (M+H).

[0356] 2-(2-((2-methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0629 (Method A, 31%) as a white powder. Rf=0.5 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 2.3 Hz, 1H), 7.75 (dd, J = 8.6, 2.3 Hz, 1H), 7.45 (dd, J = 7.9, 1.8 Hz, 1H), 7.39 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 1.8 Hz, 1H), 7.31 (s, 1H), 6.81 (d, J = 8.6 Hz, 1H), 5.42 (s, 1H), 4.89 (brs, 4H), 4.47 (t, J = 5.8 Hz, 2H), 3.98 (brs, 2H), 2.82 (t, J = 5.8 Hz, 2H), 2.64 (brs, 4H), 2.51 (brs, 4H), 2.30 (s, 3H), 2.25 (s, 3H), 1.65 (sextet, J = 7.4 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.95, 163.76, 163.31, 160.39, 151.04, 144.88, 143.52, 137.64, 137.33, 136.53, 132.76, 129.09, LCMS C 29 H 37 N9OS method (B) R t = 4.379 min, ESI+ m / z = 560.3 (M+H).

[0357] 2-((5-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)pyridin-2-yl)oxy)-1-(4-methylpiperazin-1-yl)ethan-1-one OR0630 (Method A, 3%) as a white powder. Rf=0.5 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.4 Hz, 1H), 7.80 (dd, J = 8.6, 2.4 Hz, 1H), 7.45 (dd, J = 7.9, 1.7 Hz, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 1.7 Hz, 1H), 7.36 (s, 1H), 6.96 (d, J = 8.6 Hz, 1H), 5.56 (s, 1H), 5.47 (brs, 4H), 5.05 (s, 2H), 3.97 (brs, 2H), 3.70-3.62 (m, 2H), 3.58-3.50 (m, LCMS C 29 H 35 N9O2S method (B) R t = 4.361 min, ESI+ m / z = 574.3 (M+H).

[0358] 2-(2-(methyl(4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0631 (Method B, 67%) as a pale yellow solid. Rf=0.47 (DCM-MeOH-NH4OH, 90:9:1); 1 H NMR (400 MHz, MeOD) δ 7.89 (d, J = 8.6 Hz, 2H), 7.84 (d, J = 8.6 Hz, 2H), 7.71 (d, J = 1.9 Hz, 1H), 7.69 (dd, J = 7.7, 1.9 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.29 (s, 1H), 5.54 (s, 1H), 3.60 (s, 3H), 3.09-3.01 (m, 4H), 2.54-2.46 (m, 4H), 2.32 (s, 3H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.88, 165.64, 161.18, 152.13, 146.67, 145.82, 140.49, 138.39, 135.59, 134.02, 129.67, 128.56, 128.49, 128.31, 111.39, 82.98, 55.08, 46.95, 45.75, 40.15, 17.37; LCMS C 26 H 30 N8O2S2 method (B) R t = 4.294 min, ESI+ m / z = 551.2 (M+H).

[0359] 2-(2-(ethyl(4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-di-amine OR0632 (Method B, 58%) as a light brown solid. Rf=0.36 (DCM-MeOH-NH4OH, 90:9:1); 1 H NMR (400 MHz, MeOD) δ 7.89 (d, J = 8.6 Hz, 2H), 7.84 (d, J = 8.6 Hz, 2H), 7.71 (dd, J = 8.0, 1.8 Hz, 1H), 7.66 (d, J = 1.8 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.26 (s, 1H), 5.54 (s, 1H), 4.13 (brs, 2H), 3.09-3.01 (m, 4H), 2.54-2.46 (m, 4H), 2.31 (s, 3H), 2.25 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, MeOD) δ 171.66, 165.65, 161.30, 152.12, 145.84, 144.65, 140.31, 139.18, 135.58, 134.06, 129.70, 129.56, 128.58, 128.55, 110.99, 82.98, 55.08, 47.75, 46.95, 45.75, 17.58, 13.55, LCMS C 27 H32 N8O2S2 method (B) R t = 4.418 min, ESI+ m / z = 565.2 (M+H).

[0360] 2-(2-((5-fluoro-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0633 (Method A, 11%) as a light brown solid. Rf=0.5 (DCM-MeOH-NH4OH, 90:9:1); 1 H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.40 (s, 1H), 7.32 (dd, J = 10.2, 1.6 Hz, 1H), 7.31 (d, J = 1.6 Hz, 1H), 5.57 (s, 1H), 5.40 (brs, 4H), 4.01 (brs, 2H), 3.10-3.02 (m, 4H), 2.53-2.45 (m, 4H), 2.26 (s, 3H), 2.19 (s, 3H), 1.66 (sextet, J = 7.4 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H); 19 F NMR (376 MHz, CDCl3) δ -110.83; LCMS C 28 H 33 FN8O2S2 method (B) R t = 4.384 min, ESI+ m / z = 597.2 (M+H).

[0361] 2-(2-((3'-Methoxy-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0635 (Method A, 36%) as a light brown powder. Rf=0.5 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.1 Hz, 1H), 7.53 (dd, J = 8.1, 1.9 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.35 (s, 1H), 7.20 (dd, J = 8.2, 1.4 Hz, 1H), 7.12 (d, J = 1.4 Hz, 1H), 5.49 (s, 1H), 5.10 (brs, 4H), 3.99 (brs, 2H), 3.96 (s, 3H), 3.31-3.22 (m, 4H), 2.50-2.42 (m, 4H), 2.29 (s, 3H), 2.28 (s, 3H), 1.66 (sextet, J = 7.4 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.91, 163.31, 159.37, 157.46, 150.25, 146.51, 143.59, 139.34, 138.09, 132.85, 132.48, 128.36, LCMS C 29 H 36 FN8O3S2 method (B) R t = 4.258 min, ESI+ m / z = 609.3 (M+H).

[0362] 2-(2-(isopropyl(4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0636 (Method B, 29%) as a light brown solid. Rf=0.41 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, MeOD) δ 7.88 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H), 7.73 (dd, J = 8.0, 1.9 Hz, 1H), 7.57 (d, J = 1.9 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.24 (s, 1H), 5.54 (s, 1H), 5.21 (septet, J = 6.7 Hz, 1H), 3.09-3.01 (m, 4H), 2.54-2.46 (m, 4H), 2.32 (s, 3H), 2.25 (s, 3H), 1.29-1.28 (m, 6H); 13 C NMR (100 MHz, MeOD) δ 171.77, 165.62, 161.37, 152.12, 145.82, 142.12, 140.70, 140.05, 135.57, 134.11, 130.95, 129.73, 128.86, 128.57, 110.77, 82.97, 55.07, 52.86, 46.94, 45.75, 21.46, 18.24;LCMS C 28 H 34 FN8O2S2 method (B) R t = 4.311 min, ESI+ m / z = 579.3 (M+H).

[0363] 2-(2-(isobutyl(4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0637 (Method B, 70%) as a light brown solid. Rf=0.45 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, MeOD) δ 7.88 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.69 (dd, J = 8.0, 1.7 Hz, 1H), 7.67 (d, J = 1.7 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.26 (s, 1H), 5.53 (s, 1H), 3.92 (brs, 2H), 3.09-3.01 (m, 4H), 2.54-2.46 (m, 4H), 2.31 (s, 3H), 2.25 (s, 3H), 2.06-1.96 (m, 1H), 1.03 (d, J = 6.6 Hz, 6H); 13 C NMR (100 MHz, MeOD) δ 172.66, 165.63, 161.33, 152.13, 145.90, 145.49, 140.15, 138.81, 135.57, 134.36, 129.73, 129.26, 128.58, 128.41, 111.14, 83.00, 60.51, 55.08, 46.95, 45.75, 28.72, 20.82, 17.80; LCMS C 29 H 36 FN8O2S2 method (B) R t = 4.369 min, ESI+ m / z = 593.3 (M+H).

[0364] 2-(2-((4'-((4-ethylpiperazin-1-yl)sulfonyl)-4-methyl-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0638 (Method A, 36%) as a white solid. Rf=0.5 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 8.5 Hz, 2H), 7.53 (dd, J = 7.9, 1.9 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.35 (s, 1H), 5.49 (s, 1H), 5.09 (brs, 4H), 4.00 (brs, 2H), 3.10-3.02 (m, 4H), 2.57-2.49 (m, 4H), 2.39 (q, J = 7.2 Hz, 2H), 2.28 (s, 3H), 1.67 (sextet, J = 7.4 Hz, 2H), 1.02 (t, J = 7.2 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.91, 163.32, 159.40, 150.31, 144.63, 143.58, 139.05, 138.01, 133.88, 132.96, 128.63, 128.55, LCMS C 29 H 36 FN8O2S2 method (B) R t = 4.316 min, ESI+ m / z = 593.3 (M+H).

[0365] 2-(2-((4-methyl-4'-(piperazin-1-ylsulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0639 (Method C, 53%) as a white solid. Rf=0.18 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.57 (dd, J = 7.9, 1.9 Hz, 1H), 7.51 (d, J = 1.9 Hz, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.38 (s, 1H), 5.50 (s, 1H), 5.00 (brs, 4H), 4.01 (brs, 2H), 3.10-3.02 (m, 4H), 3.01-2.94 (m, 4H), 2.30 (s, 3H), 1.69 (sextet, J = 7.2 Hz, 2H), 0.96 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 179.89, 170.95, 163.53, 159.84, 150.64, 144.57, 143.59, 139.00, 138.05, 134.28, 132.93, 128.59, 128.52, 127.57, 127.28, 111.18, 82.92, 53.89, 46.84, 45.32, 35.43, 21.34, 17.63, 11.43;LCMS C 27 H 32 N8O2S2 method (B) R t = 4.272 min, ESI+ m / z = 565.3 (M+H).

[0366] tert-Butyl 4-((3'-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4'-methyl-[1,1'-biphenyl]-4-yl)sulfonyl)piperazine-1-carboxylate OR0639-1 (Method A, 30%) as a light brown solid. 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 8.5 Hz, 2H), 7.56 (dd, J = 7.9, 1.9 Hz, 1H), 7.48 (d, J = 1.9 Hz, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.40 (s, 1H), 5.76 (brs, 4H), 5.66 (s, 1H), 4.04 (brs, 2H), 3.55-3.47 (m, 4H), 3.05-2.97 (m, 4H), 2.29 (s, 3H), 1.69 (sextet, J = 7.4 Hz, 2H), 1.39 (s, 9H), 0.97 (t, J = 7.4 Hz, 3H); LCMS C 32 H 40 N8O4S2 method (B) R t = 5.632 min, ESI+ m / z = 665.3 (M+H).

[0367] 2-(2-((4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)oxazol-4-yl)pyrimidine-4,6-diamine OR0640 (Method A, 34%) as a light brown solid. Rf=0.50 (DCM-MeOH-NH4OH, 90:10:1); 1 H NMR (400 MHz, MeOD) δ 7.86 (d, J = 8.4 Hz, 2H), 7.83 (s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 1.6 Hz, 1H), 7.59 (dd, J = 8.4, 1.6 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 5.48 (s, 1H), 3.89-3.81 (m, 2H), 3.08-3.00 (m, 4H), 2.53-2.45 (m, 4H), 2.25 (s, 3H), 2.24 (s, 3H), 1.74 (sextet, J = 7.4 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, MeOD) δ 165.48, 162.13, 159.85, 146.19, 142.81, 141.16, 139.57, 138.48, 135.45, 134.97, 133.31, 129.64, 128.61, 128.57, 127.55, 82.92, 55.09, 54.80, 46.95, 45.75, 22.39, 17.74, 11.51;LCMS C 28 H 34 N8O3S method (B) R t = 4.676 min, ESI+ m / z = 564.3 (M+H).

[0368] 2-(2-((2'-chloro-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0641 (Method A, 28%) as a pale yellow solid. Rf=0.50 (DCM-MeOH-NH4OH, 90:10:1); 1 H NMR (400 MHz, MeOD) δ 7.90 (d, J = 1.7 Hz, 1H), 7.77 (dd, J = 8.1, 1.7 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.46 (dd, J = 7.6, 1.8 Hz, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.26 (s, 1H), 5.53 (s, 1H), 3.99 (brs, 2H), 3.13-3.05 (m, 4H), 2.56-2.48 (m, 4H), 2.32 (s, 3H), 2.27 (s, 3H), 1.73 (sextet, J = 7.4 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, MeOD) δ 171.97, 165.58, 161.20, 152.02, 145.23, 144.10, 139.09, 138.78, 137.57, 134.54, 133.48, 133.36, LCMS C 28 H 33 ClN8O2S2 method (B) R t = 4.434 min, ESI+ m / z = 613.2 (M+H).

[0369] 2-(2-((4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-2'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0642 (Method A, 31% or Method B, 56%) as a pale yellow powder. Rf=0.27 (DCM-MeOH-NH4OH, 95:5:0.5); 1 H NMR (400 MHz, MeOD) δ 8.11 (d, J = 1.5 Hz, 1H), 8.07 (dd, J = 8.0, 1.5 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.35 (dd, J = 7.9, 1.4 Hz, 1H), 7.31 (d, J = 1.4 Hz, 1H), 7.26 (s, 1H), 5.53 (s, 1H), 4.00 (brs, 2H), 3.14-3.06 (m, 4H), 2.57-2.49 (m, 4H), 2.33 (s, 3H), 2.27 (s, 3H), 1.70 (sextet, J = 7.4 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, MeOD) δ 171.96, 165.63, 161.29, 152.08, 146.18, 143.87, 139.13, 137.11, 134.77, 133.23, 132.28, 131.14, LCMS C 29 H 33 F3N8O2S2 method (B) R t = 4.470 min, ESI+ m / z = 647.2 (M+H).

[0370] 2-(2-((2'-Fluoro-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0643 (Method A, 32%) as a light brown powder. Rf=0.55 (DCM-MeOH-NH4OH, 90:10:1); 1 H NMR (400 MHz, MeOD) δ 7.81-7.75 (m, 1H), 7.68-7.52 (m, 5H), 7.26 (s, 1H), 5.53 (s, 1H), 4.00 (brs, 2H), 3.13-3.05 (m, 4H), 2.56-2.48 (m, 4H), 2.32 (s, 3H), 2.27 (s, 3H), 1.73 (sextet, J = 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, MeOD) δ 171.92, 165.63, 161.29, 159.37, 152.12, 144.59, 139.43, 137.77, 135.04, 133.97, 133.78, 132.79, LCMS C 28 H33 FN8O2S2 method (B) R t = 4.322 min, ESI+ m / z = 597.3 (M+H).

[0371] 2-(2-((2'-Fluoro-6'-methoxy-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0644 (Method A, 24%) as a pale yellow solid. Rf=0.55 (DCM-MeOH-NH4OH, 90:10:1); 1 H NMR (400 MHz, MeOD) δ 7.49 (d, J = 7.9 Hz, 1H), 7.39 (d, J = 7.9 Hz, 1H), 7.35 (s, 1H), 7.28-7.20 (m, 3H), 5.53 (s, 1H), 3.99 (brs, 2H), 3.88 (s, 3H), 3.15-3.07 (m, 4H), 2.57-2.49 (m, 4H), 2.31 (s, 3H), 2.28 (s, 3H), 1.72 (sextet, J = 7.4 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, MeOD) δ 172.13, 165.61, 162.39, 161.30, 159.88, 152.01, 143.84, 138.53, 137.89, 133.05, 132.91, 131.87, LCMS C 29 H 35 FN8O3S2 method (B) R t = 4.388 min, ESI+ m / z = 627.3 (M+H).

[0372] 2-(2-((2'-Methoxy-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0645 (Method A, 28%) as a light brown solid. Rf=0.68 (DCM-MeOH-NH4OH, 90:10:1); 1 H NMR (400 MHz, MeOD) δ 7.57 (d, J = 7.9 Hz, 1H), 7.52 (dd, J = 7.9, 1.7 Hz, 1H), 7.51 (d, J = 1.7 Hz, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.44 (dd, J = 7.9, 1.7 Hz, 1H), 7.37 (d, J = 1.7 Hz, 1H), 7.25 (s, 1H), 5.54 (s, 1H), 4.02 (brs, 2H), 3.89 (s, 3H), 3.12-3.04 (m, 4H), 2.56-2.50 (m, 4H), 2.29 (s, 3H), 2.26 (s, 3H), 1.73 (sextet, J = 7.6 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, MeOD) δ 172.16, 165.50, 161.08, 158.24, 151.83, 143.86, 137.99, 137.83, 136.89, 135.50, 133.12, 132.12, LCMS C 29 H 36 FN8O3S2 method (B) R t = 4.359 min, ESI+ m / z = 609.3 (M+H).

[0373] 2-(2-((4-methyl-4'-(piperidin-4-ylsulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0646 (Method A, 28%) as a pale yellow solid. Rf=0.20 (DCM-MeOH-NH4OH, 90:10:1); 1 H NMR (400 MHz, MeOD) δ 7.95 (d, J = 8.6 Hz, 2H), 7.91 (d, J = 8.6 Hz, 2H), 7.71 (dd, J = 8.0, 1.9 Hz, 1H), 7.66 (d, J = 1.9 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.25 (s, 1H), 5.54 (s, 1H), 4.01 (brs, 2H), 3.32-3.24 (m, 1H), 3.12-3.04 (m, 2H), 2.59-2.51 (m, 2H), 2.31 (s, 3H), 1.99-1.91 (m, 2H), 1.72 (sextet, J = 7.4 Hz, 2H), 1.64-1.53 ​​(m, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, MeOD) δ 171.95, 165.63, 161.27, 152.11, 146.75, 145.05, 140.20, 139.23, 136.81, 134.17, 130.94, 129.54, 128.66, 128.59, 111.00, 82.99, 62.42, 54.89, 45.52, 26.62, 22.30, 17.63, 11.61; 28 H 33 N7O2S2 method (B) R t = 4.266 min, ESI+ m / z = 564.2 (M+H).

[0374] 2-(2-((2',6'-difluoro-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0647 (Method A, 27%) as a pale yellow solid. Rf=0.70 (DCM-MeOH-NH4OH, 90:10:1); 1 H NMR (400 MHz, MeOD) δ 7.57 (d, J = 8.0 Hz, 1H), 7.54-7.48 (m, 3H), 7.48 (s, 1H), 7.26 (s, 1H), 5.53 (s, 1H), 3.99 (brs, 2H), 3.16-3.08 (m, 4H), 2.57-2.49 (m, 4H), 2.33 (s, 3H), 2.28 (s, 3H), 1.72 (sextet, J = 7.4 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, MeOD) δ 171.90, 165.62, 162.49, 161.27, 159.90, 152.09, 144.38, 139.94, 138.60, 133.52, 132.70, 131.55, 128.50, 112.64, 111.10, 82.98, 55.07, 54.73, 46.92, 45.77, 22.21, 17.72, 11.58; LCMS C 28 H 32 N8O2S2 method (B) R t = 4.396 min, ESI+ m / z = 615.2 (M+H).

[0375] 2-(2-((4'-((4-aminopiperidin-1-yl)sulfonyl)-4-methyl-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0648 (Method C, 90%) as a pale yellow solid. Rf=0.18 (DCM-MeOH-NH4OH, 90:9:1). 1H NMR (400 MHz, MeOD) δ 7.84 (d, J = 8.6 Hz, 2H), 7.81 (d, J = 8.6 Hz, 2H), 7.67 (dd, J = 8.0, 1.5 Hz, 1H), 7.62 (d, J = 1.5 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.24 (s, 1H), 5.54 (s, 1H), 3.99 (brs, 2H), 3.74-3.66 (m, 2H), 2.60-2.52 (m, 1H), 2.43-2.35 (m, 2H), 2.28 (s, 3H), 1.89-1.81 (m, 2H), 1.71 (sextet, J = 7.4 Hz, 2H), 1.46-1.34 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, MeOD) δ 171.92, 165.62, 161.29, 152.14, 145.55, 144.99, 140.27, 138.95, 136.32, 134.13, 129.50, 129.38, 128.54, 128.48, 111.01, 83.03, 54.86, 48.72, 46.43, 34.80, 22.29, 17.64, 11.63; LCMS C 28 H 34 N8O2S2 method (B) R t = 4.317 min, ESI+ m / z = 579.3 (M+H).

[0376] tert-Butyl (1-((3'-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4'-methyl-[1,1'-biphenyl]-4-yl)sulfonyl)piperidin-4-yl)carbamate OR0648-1 (Method A, 20%) as a light brown solid. Rf=0.20 (DCM-MeOH-NH4OH, 95:5:0.5); 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 8.5 Hz, 2H), 7.57 (dd, J = 7.9, 1.8 Hz, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.41 (s, 1H), 5.70 (brs, 4H), 5.65 (s, 1H), 4.42 (brs, 1H), 4.05 (brs, 2H), 3.73 (brs, 1H), 3.40 (brs, 1H), 2.53-2.45 (m, 2H), 2.29 (s, 3H), 2.02-1.96 (m, 2H), 1.71 (sextet, J = 7.4 Hz, 2H), 1.55-1.47 (m, 2H), 1.40 (s, 9H), 0.98 (t, J = 7.4 Hz, 3H); LCMS C 33 H 42 N8O4S2 method (B) R t = 5.495 min, ESI+ m / z = 679.3 (M+H).

[0377] 2-(4-((3'-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4'-methyl-[1,1'-biphenyl]-4-yl)sulfonyl)piperazin-1-yl)acetic acid OR0649 (Method A, 20%) as a white solid. Rf=0.20 (DCM-MeOH-NH4OH, 80:18:2); 1H NMR (400 MHz, MeOD) δ 7.89 (d, J = 8.7 Hz, 2H), 7.85 (d, J = 8.7 Hz, 2H), 7.74 (dd, J = 8.0, 1.9 Hz, 1H), 7.66 (d, J = 1.9 Hz, 1H), 7.57 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 5.61 (s, 1H), 4.01 (brs, 2H), 3.17 (s, 2H), 3.16-3.12 (m, 4H), 2.86-2.80 (m, 4H), 2.31 (s, 3H), 1.74 (sextet, J = 7.4 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, MeOD) δ 174.37, 172.57, 162.36, 154.84, 146.30, 145.71, 144.52, 140.49, 138.81, 135.64, 134.31, 129.76, 129.26, 128.85, 128.64, 114.62, 81.17, 61.32, 54.98, 53.18, 46.41,22.21, 17.56, 11.73; 29 H 34 N8O4S2 method (B) R t = 4.505 min, ESI+ m / z = 623.3 (M+H).

[0378] 2-(2-((4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-3'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0650 (Method A, 40%) as a light brown solid. Rf=0.20 (DCM-MeOH-NH4OH, 95:5:0.5); 1H NMR (400 MHz, MeOD) δ 8.04 (d, J = 8.3 Hz, 1H), 7.81 (dd, J = 8.3, 1.7 Hz, 1H), 7.73-7.72 (m, 1H), 7.69 (dd, J = 7.9, 2.0 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.26 (s, 1H), 5.54 (s, 1H), 4.01 (brs, 2H), 3.27-3.19 (m, 4H), 2.53-2.45 (m, 4H), 2.31 (s, 3H), 2.28 (s, 3H), 1.73 (sextet, J = 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, MeOD) δ 171.84, 165.58, 161.18, 152.07, 148.09, 147.72, 145.17, 139.95, 138.92, 134.35, 133.68, 130.03, LCMS C 29 H 33 F3N8O3S2 method (B) R t = 4.530 min, ESI+ m / z = 663.2 (M+H).

[0379] N-(2-aminoethyl)-3'-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4'-methyl-[1,1'-biphenyl]-4-sulfonamide OR0651 (Method C, 100%) as a pale yellow solid. Rf=0.22 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, MeOD) δ 7.97 (d, J = 8.5 Hz, 2H), 7.87 (d, J = 8.5 Hz, 2H), 7.75 (dd, J = 8.0, 1.7 Hz, 1H), 7.69 (s, 1H), 7.66 (d, J = 1.7 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 5.65 (s, 1H), 4.22 (brs, 1H), 3.84 (brs, 1H), 3.18-3.12 (m, 2H), 3.12-3.04 (m, 2H), 2.32 (s, 3H), 1.75 (sextet, J = 7.4 Hz, 2H), 1.04 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, MeOD) δ 172.81, 152.43, 145.44, 144.32, 144.07, 140.64, 139.90, 138.72, 134.38, 129.13, 129.01, 128.94, 128.69, 115.92, 80.43, 54.92, 41.39, 40.67, 22.17, 17.50, 11.74. 1; LCMS C 26 H 34 F3N8O2S2 method (B) R t = 4.102 min, ESI+ m / z = 539.3 (M+H).

[0380] tert-Butyl (2-((3'-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4'-methyl-[1,1'-biphenyl])-4-sulfonamido)ethyl)carbamate OR0651-1 (Method A, 29%) as a white powder. Rf=0.6 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.51 (dd, J = 8.0, 1.7 Hz, 1H), 7.45 (d, J = 1.7 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.33 (s, 1H), 5.77 (brs, 1H), 5.50 (s, 1H), 5.12 (brs, 4H), 5.08 (brs, 1H), 3.93 (brs, 2H), 3.25-3.21 (m, 2H), 3.11-3.05 (m, 2H), 2.24 (s, 3H), 1.62 (sextet, 7.3 Hz, 2H), 1.40 (s, 9H), 0.90 (t, J = 7.3 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.92, 163.17, 156.74, 144.15, 143.47, 143.21, 139.00, 138.82, 137.80, 132.86, 128.31, 127.80, LCMS C 30 H 38 N8O4S2 method (B) R t = 4.890 min, ESI+ m / z = 639.3 (M+H).

[0381] 2-(2-((2-methyl-5-(4-methyl-6-((4-methylpiperazin-1-yl)sulfonyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0652 (Method B, 31%) as a pale yellow powder. Rf=0.23 (DCM-MeOH, 90:10); 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.82 (s, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.42 (s, 1H), 7.28 (dd, J = 7.9, 1.4 Hz, 1H), 7.20 (d, J = 1.4 Hz, 1H), 5.95 (brs, 4H), 5.69 (s, 1H), 4.04 (brs, 2H), 3.40-3.36 (m, 4H), 2.54-2.50 (m, 4H), 2.38 (s, 3H), 2.31 (s, 3H), 2.30 (s, 3H), 1.67 (sextet, J = 7.4 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.90, 161.56, 158.18, 154.50, 150.25, 147.16, 142.97, 140.78, 139.57, 137.91, 136.05, 132.93, 130.55, 129.41, 124.70, 112.64, 82.10, 54.50, 53.80, 46.57, 45.93, 21.40, 20.43,17.62, 11.50; 28 H 35 N9O2S2 method (B) R t = 4.434 min, ESI+ m / z = 594.2 (M+H).

[0382] 2-(2-((2-methyl-5-(2-methyl-6-((4-methylpiperazin-1-yl)sulfonyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0653 (Method B, 48%) as a pale yellow powder. Rf=0.23 (DCM-MeOH, 90:10); 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.36 (s, 1H), 7.24 (dd, J = 7.9, 1.8 Hz, 1H), 7.19 (d, J = 1.8 Hz, 1H), 5.53 (s, 1H), 5.20 (brs, 4H), 3.99 (brs, 2H), 3.42-3.34 (m, 4H), 2.55 (s, 3H), 2.59-2.51 (m, 4H), 2.30 (s, 3H), 2.29 (s, 3H), 1.65 (sextet, J = 7.4 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.87, 163.09, 157.39, 154.07, 149.83, 143.05, 139.16, 138.69, 138.00, 137.84, 132.69, 130.21, 129.04, 120.72, 111.51, 82.70, 54.55, 53.65, 46.76, 46.00, 23.78, 21.37, 17.60, 11.43; 28 H 35 N9O2S2 method (B) R t = 4.306 min, ESI+ m / z = 594.5 (M+H).

[0383] 2-(2-((5-(6-Methoxy-4-(trifluoromethyl)pyridin-3-yl)-2-methylphenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0654 (Method A, 25%) as a pale yellow powder. Rf=0.23 (DCM-MeOH, 90:10); 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.39 (d, J = 7.9 Hz, 1H), 7.34 (s, 1H), 7.24 (dd, J = 7.9, 1.7 Hz, 1H), 7.20 (d, J = 1.7 Hz, 1H), 7.07 (s, 1H), 5.52 (s, 1H), 5.10 (brs, 4H), 4.00 (s, 5H), 2.28 (s, 3H), 1.61 (sextet, J = 7.4 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 171.18, 164.02, 163.30, 149.81, 142.43, 138.91, 138.60, 137.51, 135.57, 132.00, 131.09, 129.79, 127.29, 124.11, 121.38, 111.49, 107.99, 82.75, 54.18, 53.46, 21.23, 17.54, 11.41; LCMS C 24 H 24 F3N7OS method (B) R t = 5.882 min, ESI+ m / z = 516.2 (M+H).

[0384] 2-(2-((5-(6-hydroxy-4-(trifluoromethyl)pyridin-3-yl)-2-methylphenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0655 (Method A, 95%) as a pale yellow powder. Rf=0.66 (DCM-MeOH-NH4OH, 80:18:2); 1H NMR (400 MHz, MeOD) δ 7.60 (s, 1H), 7.50 (s, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.34 (dd, J = 7.9, 2.0 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 6.91 (s, 1H), 5.64 (s, 1H), 4.01 (brs, 2H), 2.30 (s, 3H), 1.70 (sextet, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, MeOD) δ 172.71, 163.90, 154.10, 145.52, 143.34, 142.64, 138.86, 138.58, 135.95, 133.42, 132.26, 131.93, 124.99, 122.25, 119.06, 118.28, 115.05, 80.92, 54.68, 22.08, 17.47, 11.70. 23 H 22 F3N7OS method (B) R t = 4.323 min, ESI+ m / z = 502.2 (M+H).

[0385] 2-(2-((2-methyl-5-(6-((4-methylpiperazin-1-yl)sulfonyl)-4-(trifluoromethyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0656 (Method B, 59%) as a pale yellow powder. Rf=0.23 (DCM-MeOH, 90:10); 1H NMR (400 MHz, MeOD) δ 8.84 (s, 1H), 8.22 (s, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.44 (dd, J = 8.2, 1.9 Hz, 1H), 7.42 (d, J = 1.9 Hz, 1H), 7.33 (s, 1H), 5.55 (s, 1H), 4.00 (brs, 2H), 3.42-3.36 (m, 4H), 2.56-2.50 (m, 4H), 2.35 (s, 3H), 2.31 (s, 3H), 1.71 (sextet, J = 7.5 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 171.98, 164.96, 159.93, 157.81, 154.42, 150.90, 144.11,140.02, 138.84, 135.45, 133.60, 131.68, LCMS C 28 H 32 F3N9O2S2 method (B) R t = 4.511 min, ESI+ m / z = 648.2 (M+H).

[0386] 2-(2-((2-methyl-5-(6-((4-methylpiperazin-1-yl)sulfonyl)-2-(trifluoromethyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0657 (Method B, 55%) as a pale yellow powder. Rf=0.23 (DCM-MeOH, 90:10); 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.37 (s, 1H), 7.26 (dd, J = 7.9, 1.9 Hz, 1H), 7.23 (d, J = 1.9 Hz, 1H), 5.54 (s, 1H), 5.28 (brs, 4H), 3.99 (brs, 2H), 3.50-3.44 (m, 4H), 2.54-2.48 (m, 4H), 2.31 (s, 3H), 2.30 (s, 3H), 1.62 (sextet, J = 7.4 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.83, 162.95, 155.47, 145.45, 145.11, 142.77, 142.57, 139.06, 138.86, 135.16, 132.47, 130.07, LCMS C 28 H 32 F3N9O2S2 method (B) R t = 4.601 min, ESI+ m / z = 648.2 (M+H).

[0387] 2-(2-((2-methyl-5-(6-(piperazin-1-ylsulfonyl)-2-(trifluoromethyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0658 (Method C, 65%) as a pale yellow powder. Rf=0.18 (DCM-MeOH, 90:10); 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.1 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.36 (s, 1H), 7.26 (dd, J = 7.9, 1.9 Hz, 1H), 7.26 (d, J = 1.9 Hz, 1H), 5.45 (s, 1H), 5.00 (brs, 4H), 3.97 (brs, 2H), 3.46-3.40 (m, 4H), 3.00-2.94 (m, 4H), 2.31 (s, 3H), 1.62 (sextet, J = 7.5 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.81, 163.41, 159.60, 155.57, 150.36, 145.40, 142.82, 142.61, 139.07, 138.90, 135.14, 132.45, 130.08, 128.70, 124.98, 121.22, 111.48, 82.82, 53.74, 47.70, 45.70, 21.21,17.69, 11.38; 27 H 30 F3N9O2S2 method (B) R t = 4.308 min, ESI+ m / z = 634.2 (M+H).

[0388] General procedure for the synthesis of 2-(2-((5-halogeno-2-methylphenyl)(alkyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine. As previously described for the synthesis of 2-[2-(biaryl-3-ylamino)-thiazol-4-yl]-pyrimidine-4,6-diamine derivatives, method (A).

[0389] 2-(2-((5-iodo-2-methylphenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0607-1 (40%) as a pale yellow solid. Rf=0.30 (DCM-MeOH-NH4OH, 95:5:0.5); 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J = 8.1, 1.7 Hz, 1H), 7.55 (d, J = 1.7 Hz, 1H), 7.36 (s, 1H), 7.06 (d, J = 8.1 Hz, 1H), 5.50 (s, 1H), 5.08 (brs, 4H), 3.97-3.89 (m, 2H), 2.17 (s, 3H), 1.60 (sextet, J = 7.4 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.59, 163.34, 159.47, 150.29, 144.20, 138.28, 137.65, 137.58, 133.74, 111.53, 90.93, 82.85, 53.91, 21.22, 17.54, 11.37; LCMS C 17 H 19 N6S method (B) R t = 5.226 points, ESI+ m / z = 467.0 (M+H).

[0390] 2-(2-((5-ブロモ-2-メチルフェニル)アミノ)チアゾール-4-イル)ピリミジン-4,6-ジアミンOR0614-1 (23%), thin brown solid として. Rf=0.15(DCM-MeOH-NH4OH, 95:5:0.5); 1 H NMR (400 MHz, MeOD) δ 7.87 (d, J = 1.8 Hz, 1H), 7.46 (s, 1H), 7.19 (dd, J = 8.1, 1.8 Hz, 1H), 7.15 (d, J = 8.1 Hz, 1H), 5.54 (s, 1H), 2.27 (s, 3H); LCMS C 14 H 13 BrN6S method (B) R t = 4.752 points, ESI+ m / z = 337.0 (M+H).

[0391] 2-(2-((5-bromo-2-methylphenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0652-1 (36%) as a pale yellow solid. Rf=0.35 (DCM-MeOH-NH4OH, 95:5:0.5); 1 H NMR (400 MHz, CDCl3) δ 7.41 (dd, J = 8.2, 2.0 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.35 (s, 1H), 7.20 (d, J = 8.2 Hz, 1H), 5.46 (s, 1H), 5.01 (brs, 4H), 3.95-3.87 (m, 2H), 2.16 (s, 3H), 1.60 (sextet, J = 7.4 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H); LCMS C 17 H 19 BrN6S method (B) R t = 5.340 min, ESI+ m / z = 419.0 (M+H).

[0392] 2-(2-((5-bromo-2-methylphenyl)(methyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0631-1 (50%) as a light brown solid. Rf=0.60 (DCM-MeOH-NH4OH, 90:10:1); 1 H NMR (400 MHz, MeOD) δ 7.51 (d, J = 2.0 Hz, 1H), 7.49 (dd, J = 8.3, 2.0 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.30 (s, 1H), 5.53 (s, 1H), 3.51 (s, 3H), 2.22 (s, 3H); LCMS C 15 H 15 BrN6S method (B) R t = 5.129 min, ESI+ m / z = 391.0 (M+H).

[0393] 2-(2-((5-bromo-2-methylphenyl)(ethyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0632-1 (40%) as a light brown solid. Rf=0.45 (DCM-MeOH-NH4OH, 90:9:1); 1 H NMR (400 MHz, MeOD) δ 7.49 (dd, J = 8.1, 2.0 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.29 (s, 1H), 5.53 (s, 1H), 4.04 (q, J = 7.1 Hz, 2H), 2.20 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, MeOD) δ 171.20, 165.46, 160.93, 151.84, 145.16, 138.02, 134.70, 133.57, 132.92, 120.94, 111.38, 82.94, 47.83, 17.37, 13.40; LCMS C 16 H 17 BrN6S method (B) R t = 5.205 min, ESI+ m / z = 405.0 (M+H).

[0394] 2-(2-((5-bromo-2-methylphenyl)(isopropyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0636-1 (35%) as a pale yellow solid. Rf=0.45 (DCM-MeOH-NH4OH, 90:9:1); 1 H NMR (400 MHz, MeOD) δ 7.53 (dd, J = 8.3, 2.1 Hz, 1H), 7.41 (d, J = 2.1 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.28 (s, 1H), 5.54 (s, 1H), 5.13 (Septet, J = 6.7 Hz, 1H), 2.21 (s, 3H), 1.24 (d, J = 6.7 Hz, 6H); 13C NMR (100 MHz, MeOD) δ 171.34, 165.39, 160.85, 151.69, 142.68, 139.55, 134.95, 134.74, 133.26, 120.67, 111.20, 82.85, 53.00, 21.21, 17.96; LCMS C 17 H 19 BrN6S method (B) R t = 5.252 min, ESI+ m / z = 419.0 (M+H).

[0395] 2-(2-((5-bromo-2-methylphenyl)(isobutyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0637-1 (40%) as a light brown solid. Rf=0.45 (DCM-MeOH-NH4OH, 90:9:1); 1 H NMR (400 MHz, MeOD) δ 7.51-7.47 (m, 2H), 7.32 (d, J = 8.8 Hz, 1H), 7.28 (s, 1H), 5.53 (s, 1H), 3.84 (brs, 2H), 2.21 (s, 3H), 2.02-1.89 (m, 1H), 1.01 (d, J = 6.7 Hz, 6H); 13 C NMR (100 MHz, MeOD) δ 172.24, 165.59, 161.19, 152.04, 146.07, 137.69, 135.00, 133.30, 132.76, 120.84, 111.40, 82.98, 60.56, 28.64, 20.71, 17.59; LCMS C 18 H 21 BrN6S method (B) R t = 5.382 min, ESI+ m / z = 433.0 (M+H).

[0396] General procedure for the synthesis of ethyl 2-([1,1'-biaryl]-3-ylamino)thiazole-4-carboxylate derivatives. Method (A): As previously described for dCKi-2-1, to a stirred solution of the appropriate 1-([1,1'-biaryl]-3-yl)thiourea (10.0 mmol) in ethanol (100 mL) was added ethyl bromopyruvate (1.5 mL, 12.0 mmol). The resulting mixture was heated at reflux for 3 h, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography to give the expected ethyl 2-([1,1'-biaryl]-3-ylamino)thiazole-4-carboxylate derivative. Method (B): Under argon, a suspension of the appropriate aryl halide (1 mmol), ethyl 2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)thiazole-4-carboxylate or analog (1.1 mmol), PdCl(dppf) (36 mg, 0.05 mmol), and NaCO (212 mg, 2 mmol) in a degassed mixture of 1,4-dioxane and water (5:1, 12 mL) was refluxed for 2 h after complete consumption of the starting material. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography to give the corresponding ethyl 2-([1,1'-biaryl]-3-ylamino)thiazole-4-carboxylate derivative or analog. Method (C): To a solution of 4-halogenoarylsulfonyl chloride (1.0 mmol) in 1,4-dioxane (12 mL) under argon, the appropriate amine (1.15 mmol) and K2CO3 (3.0 mmol) were added successively. The reaction mixture was stirred at room temperature until the starting material was completely consumed, as monitored by LCMS. To the resulting suspension, ethyl 2-((2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(propyl)amino)thiazole-4-carboxylate OR0625-2 (1.10 mmol), PdCl2(dppf) (0.15 mmol), and water (2 mL) were added successively. The reaction mixture was thoroughly degassed several times under a blanket of argon and then heated at 80 °C for 2 h. The solvent was evaporated, and the residue was triturated with DCM (3 × 50 mL).The combined organic layers were dried over Na2SO4, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography to give the expected ethyl 2-([1,1'-biaryl]-3-ylamino)thiazole-4-carboxylate.

[0397] Ethyl 2-((4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazole-4-carboxylate OR0600-1 (Method A, 86%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.53 (dd, J = 8.0, 1.9 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 1.9 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.29 (s, 1H), 7.28 (d, J = 8.2 Hz, 2H), 4.36 (q, J = 7.1 Hz, 2H), 3.85 (brs, 2H), 2.88-2.80 (m, 2H), 2.67-2.59 (m, 2H), 2.50 (brs, 8H), 2.31 (s, 3H), 2.25 (s, 3H), 1.69 (sextet, J = 7.4 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H); LCMS C 29 H 38 N4O2S method (B) R t = 5.102 min, ESI+ m / z = 507.3 (M+H).

[0398] 2-((4-methyl-4'-(3-(4-methylpiperazin-1-yl)propyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazole-4-carboxylate OR0601-1 (Method A, 93%) as a beige foam. Rf=0.35 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, CDCl3) δ 7.53 (dd, J = 7.9, 1.9 Hz, 1H), 7.48 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 1.9 Hz, 1H), 7.39 (d, J = 7.9 Hz, 1H), 7.28 (s, 1H), 7.24 (d, J = 8.1 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 3.93 (brs, 2H), 2.73 (brs, 8H), 2.72-2.64 (m, 2H), 2.54-2.46 (m, 2H), 2.44 (s, 3H), 2.25 (s, 3H), 1.90 (quintet, J = 7.6 Hz, 2H), 1.69 (sextet, J = 7.4 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 170.89, 162.09, 143.97, 143.18, 141.20, 140.96, 137.65, 135.87, 132.68, 129.06, 127.83, 127.24, LCMS C 30 H 40 N4O2S method (B) R t = 5.158 min, ESI+ m / z = 521.4 (M+H).

[0399] Ethyl 2-((2-methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethyl)pyridin-3-yl)phenyl)(propyl)amino)thiazole-4-carboxylate OR0602-1 (Method A, 47%) as a light brown oil. LCMS C 28 H 37 N5O2S, method (B)R t =4.730 min, ESI+m / z=508.2(M+H).

[0400] Ethyl 2-(isobutyl(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazole-4-carboxylate OR0603-1 (Method A, 57%) as a light brown solid. LCMS C 30 H 40 N4O2S, method (B)R t =5.363 min, ESI+m / z=521.2(M+H).

[0401] Ethyl 2-((cyclopropylmethyl)(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazole-4-carboxylate OR0604-1 (Method A, 100%) as a yellow solid. LCMS C 30 H 38 N4O2S, method (B)R t =5.138 min, ESI+m / z=519.3(M+H).

[0402] Ethyl 2-(isopentyl(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazole-4-carboxylate OR0605-1 (Method A, 31%) as a pale yellow solid. Rf=0.45 (DCM-MeOH-NH4OH, 90:9:1); LCMS C 31 H 42 N4O2S, method (B)R t =5.460 min, ESI+m / z=535.3(M+H).

[0403] Ethyl 2-(butyl(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazole-4-carboxylate OR0606-1 (Method A, 89%), used in the next step without further purification as a pale yellow solid. Rf=0.45 (DCM-MeOH, 90:10); 1H NMR (400 MHz, CDCl3) δ 7.53 (dd, J = 8.0, 1.9 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 1.9 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.28 (d, J = 8.2 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 3.96 (brs, 2H), 2.90-2.82 (m, 2H), 2.72-2.64 (m, 2H), 2.58 (brs, 8H), 2.37 (s, 3H), 2.25 (s, 3H), 1.63 (quintet, J = 7.8 Hz, 2H), 1.42-1.34 (m, 2H), 1.38 (t, J = 7.1 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 170.89, 162.11, 143.97, 143.20, 140.95, 139.72, 137.86, 135.94, 132.70, 129.40, 127.87, 127.26, 127.01, 116.75, 61.12, 60.21, 54.93, 52.71, 51.88, 45.79, 33.18, 30.06, 20.26, 17.40,14.49, 14.04; 30 H 40 N4O2S method (B) R t = 5.117 min, ESI+ m / z = 521.3 (M+H).

[0404] Ethyl 2-(isobutyl(2-methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-3-yl)phenyl)amino)thiazole-4-carboxylate OR0608-1 (Method A, 100%) as a light brown solid. LCMS C 29 H 39 N5O3S, method (B)R t =5.274 min, ESI+m / z=538.2(M+H).

[0405] Ethyl 2-(isobutyl(2-methyl-5-(4-(methylsulfonamidomethyl)-1H-1,2,3-triazol-1-yl)phenyl)amino)thiazole-4-carboxylate OR0609-1 (Method A, 38%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.64 (dd, J = 8.3, 2.0 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.34 (s, 1H), 5.22 (brs, 1H), 4.52 (s, 2H), 4.34 (q, J = 7.1 Hz, 2H), 3.81 (brs, 2H), 3.01 (s, 3H), 2.29 (s, 3H), 2.06-2.00 (m, 1H), 1.36 (t, J = 7.1 Hz, 3H), 0.99 (d, J = 6.8 Hz, 6H); LCMS C 21 H 28 N6O4S2 method (B) R t = 6.189 min, ESI+ m / z = 493.2 (M+H).

[0406] Ethyl 2-((2-((tert-butoxycarbonyl)amino)ethyl)(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazole-4-carboxylate OR0610-2 (Method A, 399 mg, 74%) as a pale yellow solid. Rf=0.47 (DCM-MeOH, 90:10); 1H NMR (400 MHz, CDCl3) δ 7.53 (dd, J = 7.9, 1.8 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 1.8 Hz, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.30 (s, 1H), 7.25 (d, J = 8.2 Hz, 2H), 5.56 (brs, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.55-3.47 (m, 2H), 2.88-2.80 (m, 2H), 2.69-2.61 (m, 2H), 2.58 (brs, 8H), 2.35 (s, 3H), 2.23 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H), 1.35 (s, 9H); LCMS C 33 H 45 N5O4S method (B) R t = 5.147 min, ESI+ m / z = 608.3 (M+H).

[0407] Ethyl 2-((3-((tert-butoxycarbonyl)amino)propyl)(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazole-4-carboxylate OR0611-2 (Method A, 67%) as a pale yellow solid. Rf=0.55 (DCM-MeOH, 90:10); 1H NMR (400 MHz, CDCl3) δ 7.54 (dd, J = 8.0, 1.8 Hz, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 1.8 Hz, 1H), 7.29 (s, 1H), 7.27 (d, J = 8.2 Hz, 2H), 6.25 (brs, 1H), 4.39 (q, J = 6.9 Hz, 2H), 4.29 (brs, 1H), 3.70 (brs, 1H), 3.42-3.34 (m, 2H), 3.28-3.20 (m, 2H), 2.89-2.81 (m, 2H), 2.71-2.63 (m,2H), 2.62 (brs, 8H), 2.39 (s, 3H), 2.24 (s, 3H), 1.83-1.75 (m, 2H), 1.46 (s, 9H), 1.39 (t, J = 6.9 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 171.27, 161.95, 156.50, 143.61, 143.10, 141.30, 139.72, 137.70, 135.42, 132.93, 129.39, 127.90, LCMS C 34 H 47 N5O4S method (B) R t = 5.401 min, ESI+ m / z = 622.4 (M+H).

[0408] Ethyl 2-((2-methyl-5-(6-(4-methylpiperazine-1-carbonyl)pyridin-3-yl)phenyl)(propyl)amino)thiazole-4-carboxylate OR0612-1 (Method A, 62%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 2.0 Hz, 1H), 7.97 (dd, J = 8.2, 2.0 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.56 (dd, J = 8.0, 1.9 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.30 (s, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.94 (brs, 4H), 3.81 (brs, 2H), 2.68 (brs, 2H), 2.60 (brs, 2H), 2.44 (s, LCMS C 27 H 33 N5O3S method (B) R t = 5.007 min, ESI+ m / z = 508.2 (M+H).

[0409] Ethyl 2-((2-methyl-5-(6-(4-methylpiperazine-1-carboxamido)pyridin-3-yl)phenyl)(propyl)amino)thiazole-4-carboxylate OR0616-1 (Method A, 45%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 2.3 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.85 (dd, J = 8.7, 2.3 Hz, 1H), 7.50 (dd, J = 8.0, 1.9 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 1.9 Hz, 1H), 7.30 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.91 (brs, 2H), 3.75 (brs, 4H), 2.73 (brs, 4H), 2.51 (s, 3H), 2.26 (s, 3H), 1.69 (sextet, J = 7.4 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H); LCMS C 27 H 34 N6O3S method (B) R t = 5.089 min, ESI+ m / z = 523.3 (M+H).

[0410] Ethyl 2-((2-methyl-5-(6-((4-methylpiperazine)-1-sulfonamido)pyridin-3-yl)phenyl)(propyl)amino)thiazole-4-carboxylate OR0625-1 (Method B, 41%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 2.2 Hz, 1H), 7.88 (dd, J = 9.1, 2.2 Hz, 1H), 7.54 (d, J = 9.1 Hz, 1H), 7.47 (dd, J = 8.0, 1.7 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 1.7 Hz, 1H), 7.31 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.91 (brs, 2H), 3.53 (brs, 4H), 2.91 (brs, 4H), 2.56 (s, 3H), 2.27 (s, 3H), 1.69 (sextet, J = 7.4 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H); LCMS C 26 H 34 N6O4S2 method (B) R t = 5.084 min, ESI+ m / z = 559.3 (M+H).

[0411] Ethyl 2-((2-methyl-5-(6-((4-methylpiperazin-1-yl)sulfonyl)pyridin-3-yl)phenyl)(propyl)amino)thiazole-4-carboxylate OR0627-1 (Method B, 68%) as a light brown solid. Rf=0.50 (DCM-MeOH, 95:5); 1H NMR (400 MHz, CDCl3) δ 8.88 (d, J = 2.2 Hz, 1H), 8.04 (dd, J = 8.1, 2.2 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.56 (dd, J = 7.9, 1.9 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.31 (s, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.94 (brs, 2H), 3.46 (brs, 4H), 2.63 (brs, 4H), 2.39 (s, 3H), 2.30 (s, 3H), 1.70 (sextet, J = 7.4 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.37, 161.98, 154.68, 148.45, 144.14, 143.85, 138.78, 138.61, 136.00, 135.83, 133.53, 128.51, 127.59, 123.26, 116.90, 61.21, 54.34, 53.90, 46.13, 24.99, 21.27, 17.63, 14.49, 11.43;LCMS C 26 H 33 N5O4S2 method (B) R t = 5.281 min, ESI+ m / z = 544.2 (M+H).

[0412] Ethyl 2-((2-methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-3-yl)phenyl)(propyl)amino)thiazole-4-carboxylate OR0629-1 (Method B, 84%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 2.3 Hz, 1H), 7.75 (dd, J = 8.7, 2.3 Hz, 1H), 7.47 (dd, J = 7.9, 1.9 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 1.9 Hz, 1H), 7.29 (s, 1H), 6.82 (d, J = 8.7 Hz, 1H), 4.48 (t, J = 5.8 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 3.89 (brs, 2H), 2.84 (t, J = 5.8 Hz, 2H), 2.71 (brs, 4H), 2.62 (brs, 4H), 2.37 (s, 3H), 2.25 (s, 3H), 1.69 (sextet, J = 7.4 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H); LCMS C 28 H 37 N5O3S method (B) R t = 5.247 min, ESI+ m / z = 524.3 (M+H).

[0413] Ethyl 2-((2-methyl-5-(6-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy)pyridin-3-yl)phenyl)(propyl)amino)thiazole-4-carboxylate OR0630-1 (Method B, 71%) as a light brown oil. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 2.4 Hz, 1H), 7.79 (dd, J = 8.6, 2.4 Hz, 1H), 7.47 (dd, J = 8.0, 1.8 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 1.8 Hz, 1H), 7.29 (s, 1H), 6.96 (d, J = 8.6 Hz, 1H), 5.05 (s, 2H), 4.35 (q, J = 7.1 Hz, 2H), 3.91 (brs, 2H), 3.74 (brs, 2H), 3.63 (brs, 2H), , 2.62-2.50 (m, 4H), 2.40 (s, 3H), 2.25 (s, 3H), 1.69 (sextet, J = 7.4 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H); LCMS C 28 H 35 N5O4S method (B) R t = 5.234 min, ESI+ m / z = 538.3 (M+H).

[0414] Ethyl 2-((5-fluoro-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazole-4-carboxylate OR0633-1 (Method A, 86%) as a yellow oil. LCMS C 27 H 33 FN4O4S2, Method (B)R t =5.584 min, ESI+m / z=561.2(M+H).

[0415] Ethyl 2-((3'-methoxy-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazole-4-carboxylate OR0635-1 (Method B, 82%) as a light brown solid. Rf=0.50 (DCM-MeOH, 95:5); 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.0 Hz, 1H), 7.55 (dd, J = 8.0, 1.9 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.31 (s, 1H), 7.20 (dd, J = 8.2, 1.4 Hz, 1H), 7.12 (d, J = 1.4 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.99 (s, 3H), 3.97 (brs, 2H), 3.44 (brs, 4H), 2.70 (brs, 4H), 2.46 (s, LCMS C 28 H 36 FN4O5S2 method (B) R t = 5.258 min, ESI+ m / z = 574.3 (M+H).

[0416] Ethyl 2-((4'-((4-ethylpiperazin-1-yl)sulfonyl)-4-methyl-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazole-4-carboxylate OR0638-1 (Method B, 82%) as a colorless oil. LCMS C 28 H 36 N4O4S2, method (B)R t =5.183 min, ESI+m / z=557.4(M+H).

[0417] Ethyl 2-((4'-((4-(tert-butoxycarbonyl)piperazin-1-yl)sulfonyl)-4-methyl-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazole-4-carboxylate OR0639-2 (Method B, 56%) as a white solid. LCMS C 31 H 40 N4O6S2, method (B)R t =7.658 minutes.

[0418] Ethyl 2-((4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)oxazole-4-carboxylate OR0640-1 (Method B, 78%) as a light brown solid. 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H), 7.69 (s, 1H), 7.50 (dd, J = 7.8, 1.8 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 1.8 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.87-3.79 (m, 2H), 3.18 (brs, 4H), 2.66 (brs, 4H), 2.40 (s, 3H), 2.24 (s, 3H), 1.70 (sextet, J = 7.4 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 182.08, 162.14, 160.86, 151.89, 145.03, 140.97, 139.05, 138.45, 138.17, 137.34, 134.13, 133.42, LCMS C 27 H 34 N4O5S method (B) R t = 5.157 min, ESI+ m / z = 527.3 (M+H).

[0419] Ethyl 2-((2'-chloro-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazole-4-carboxylate OR0641-1 (Method B, 73%) as a light brown solid. Rf=0.50 (DCM-MeOH, 95:5);1 H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 1.8 Hz, 1H), 7.67 (dd, J = 8.0, 1.8 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.37 (dd, J = 7.9, 1.8 Hz, 1H), 7.33 (d, J = 1.8 Hz, 1H), 7.30 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.93 (brs, 2H), 3.13-3.11 (m, 4H), 2.55-2.54 (m, 4H), 2.31 (s, 3H), 2.29 (s, 3H), 1.68 (sextet, J = 7.4 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.64, 162.03, 144.03, 143.81, 142.63, 137.88, 137.41, 135.82, 133.75, 132.47, 131.86, 130.68, 129.53, 129.39, 126.31, 116.90, 61.15, 54.02, 53.66, 45.93, 45.67, 21.18, 17.56,14.48, 11.43; 27 H 33 ClN4O4S2 method (B) R t = 5.248 min, ESI+ m / z = 577.2 (M+H).

[0420] Ethyl 2-((4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-2'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazole-4-carboxylate OR0642-1 (Method B, 75%) as a light brown solid. Rf=0.65 (DCM-MeOH, 95:5); 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 1.6 Hz, 1H), 7.93 (dd, J = 8.0, 1.6 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.31 (s, 1H), 7.28 (dd, J = 7.9, 1.4 Hz, 1H), 7.20 (d, J = 1.4 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.93 (brs, 2H), 3.16-3.13 (m, 4H), 2.59-2.56 (m, 4H), 2.34 (s, 3H), 2.29 (s, 3H), 1.66 (sextet, J = 7.4 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.66, 162.04, 144.82, 144.01, 142.40, 137.96, 137.71, 135.41, 133.15, 132.28, 130.68, 129.99, 129.67, 129.01, 125.89, 116.98, 61.16, 53.97, 53.61, 45.82, 45.62, 21.13, 17.54, 14.48, 11.42; 28 H 33 F3N4O4S2 method (B) R t = 5.454 min, ESI+ m / z = 611.3 (M+H).

[0421] Ethyl 2-((2'-fluoro-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazole-4-carboxylate OR0643-1 (Method B, 62%) as a light brown solid. Rf=0.50 (DCM-MeOH, 95:5); 1H NMR (400 MHz, CDCl3) δ 7.61-7.60 (m, 2H), 7.53-7.51 (m, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.31 (s, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.93 (brs, 2H), 3.23-3.20 (m, 4H), 2.69-2.67 (m, 4H), 2.42 (s, 3H), 2.29 (s, 3H), 1.70 (sextet, J = 7.4 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.61, 162.05, 148.86, 144.08, 143.16, 138.30, 136.18, 133.69, 132.82, 131.46, 130.32, 129.31, LCMS C 27 H 33 FN4O4S2 method (B) R t = 5.220 min, ESI+ m / z = 561.2 (M+H).

[0422] Ethyl 2-((2',6'-difluoro-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazole-4-carboxylate OR0644-1 (Method B, 64%) as a pale yellow solid. Rf=0.28 (DCM-MeOH, 98:2); 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.41- 7.32 (m, 3H), 7.31 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.91 (brs, 2H), 3.16-3.13 (m, 4H), 2.56-2.54 (m, 4H), 2.32 (s, 3H), 2.30 (s, 3H), 1.68 (sextet, J = 7.4 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.61, 162.04, 161.10, 158.57, 144.01, 142.90, 138.76, 136.73, 132.58, 131.60, 130.51, 127.08, 117.00, 111.60, 61.16, 54.00, 53.67, 45.68, 44.61, 21.12, 17.64, 14.47, 11.40; LCMS C 27 H 32 F2N4O4S2 method (B) R t = 5.283 min, ESI+ m / z = 579.2 (M+H).

[0423] Ethyl 2-((2'-methoxy-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazole-4-carboxylate OR0645-1 (Method B, 55%) as a light brown solid. Rf=0.35 (DCM-MeOH, 95:5); LCMS C 28 H 36 N4O5S2, method (B)R t =5.291 min, ESI+m / z=573.2(M+H).

[0424] Ethyl 2-((4-methyl-4'-(piperidin-4-ylsulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazole-4-carboxylate OR0646-1 (Method B, 70%) as a light brown solid. Rf=0.25 (DCM-MeOH, 95:5); 1 H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.5 Hz, 2H), 7.74 (d, J = 8.5 Hz, 2H), 7.58 (dd, J = 8.0, 1.9 Hz, 1H), 7.48 (d, J = 1.9 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.30 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.95 (brs, 2H), 3.30-3.24 (m, 2H), 3.12 -3.02 (m, 1H), 2.70-2.62 (m, 2H), 2.29 (s, 3H), 2.13-2.05 (m, 2H), 1.76-1.65 (m, 4H), 1.38 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 170.56, 162.03, 145.57, 144.10, 143.58, 139.02, 138.09, 135.40, 133.19, 129.96, 128.48, 127.74, 127.67, 116.84, 61.34, 61.21, 53.88, 44.70, 25.33, 21.25, 17.57, 14.49, 11.45; LCMS C 27 H 33 N3O4S2 method (B) R t = 5.135 min, ESI+ m / z = 528.2 (M+H).

[0425] Ethyl 2-((4'-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)-4-methyl-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazole-4-carboxylate OR0648-2 (Method B, 88%) as a colorless oil. Rf=0.50 (DCM-MeOH, 98:2); 1 H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.3 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.58 (dd, J = 8.0, 1.5 Hz, 1H), 7.48 (d, J = 1.5 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.30 (s, 1H), 4.41 (brs, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.95 (brs, 2H), 3.73 (brs, 1H), 3.39 (brs, 1H), 2.52-2.43 (m, 2H), 2.29 (s, 3H), 2.02-1.95 (m, 2H), 1.71 (sextet, J = 7.4 Hz, 2H), 1.53-1.47 (m, 2H), 1.40 (s, 9H), 1.37 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H); LCMS C 32 H 42 N4O6S2 method (B) R t = 7.522 min, ESI+ m / z = 643.2 (M+H).

[0426] 2-(4-((3'-((4-(ethoxycarbonyl)thiazol-2-yl)(propyl)amino)-4'-methyl-[1,1'-biphenyl]-4-yl)sulfonyl)piperazin-1-yl)acetic acid OR0649-1 (Method B, 42%) as a white solid. Rf=0.11 (DCM-MeOH, 95:5); 1H NMR (400 MHz, MeOD) δ 7.91 (d, J = 8.8 Hz, 2H), 7.87 (d, J = 8.8 Hz, 2H), 7.73 (dd, J = 8.0, 1.9 Hz, 1H), 7.64 (d, J = 1.9 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.45 (s, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.91 (brs, 2H), 3.36 (s, 2H), 3.21 (brs, 4H), 3.03 (brs, 4H), 2.29 (s, 3H), 1.74 (sextet, J = 7.4 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, MeOD) δ 172.17, 163.30, 145.93, 144.85, 144.66, 140.42, 138.85, 135.45, 134.29, 129.78, 129.26, 128.78, 128.72, 118.30, 62.13, 59.86, 55.21, 53.01, 45.86, 22.14, 17.52, 14.60, 11.55; LCMS C 28 H 34 N4O6S2 method (B) R t = 5.694 min, ESI+ m / z = 588.3 (M+H).

[0427] Ethyl 2-((4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-3'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazole-4-carboxylate OR0650-1 (Method B, 82%) as a white solid. Rf=0.36 (DCM-MeOH, 95:5); 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.2 Hz, 1H), 7.56 (dd, J = 8.2, 1.6 Hz, 1H), 7.54-7.52 (m, 1H), 7.53 (dd, J = 8.0, 2.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.31 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.94 (brs, 2H), 3.28 (brs, 4H), 2.50 (brs, 4H), 1.68 (sextet, J = 7.4 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.41, 161.96, 146.72, 146.54, 144.11, 143.67, 138.66, 137.98, 133.32, 132.53, 128.87, 128.33, LCMS C 28 H 33 F3N4O5S2 method (B) R t = 5.512 min, ESI+ m / z = 627.2 (M+H).

[0428] Ethyl 2-((4'-(N-(2-((tert-butoxycarbonyl)amino)ethyl)sulfamoyl)-4-methyl-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazole-4-carboxylate OR0651-2 (Method B, 66%) as a colorless oil. Rf=0.33 (DCM-MeOH, 95:5); 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.57 (dd, J = 7.8, 1.5 Hz, 1H), 7.47 (d, J = 1.5 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.30 (s, 1H), 5.40 (brs, 1H), 4.91 (brs, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.95 (brs, 2H), 3.28-3.20 (m, 2H), 3.14-3.06 (m, 2H), 2.28 (s, 3H), 1.70 (sextet, J = 7.4 Hz, 2H), 1.41 (s, 9H), 1.37 (t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.61, 161.99, 156.74, 144.22, 143.98, 143.48, 139.28, 138.92, 137.72, 133.12, 128.32, 127.84, LCMS C 29 H 38 N4O6S2 method (B) R t = 7.124 min, ESI+ m / z = 603.3 (M+H).

[0429] General procedure for the synthesis of 1-([1,1'-biaryl]-3-yl)thiourea derivatives. As previously described above for 1-(3-nitroaryl)thiourea derivatives.

[0430] 1-Isobutyl-1-(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)thiourea OR0603-2 (95%) as a white solid. LCMS C 25 H 36N4S, Method (B)R t =4.591 min, ESI+m / z=425.3(M+H).

[0431] 1-(Cyclopropylmethyl)-1-(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)thiourea OR0604-2 (70%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.53 (dd, J = 8.0, 1.9 Hz, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 1.9 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.1 Hz, 2H), 5.52 (brs, 2H), 4.38-4.32 (m, 1H), 3.82-3.74 (m, 1H), 2.86-2.82 (m, 2H), 2.67-2.61 (m, 2H), 2.50 (brs, 8H), 2.31 (s, 3H), 2.29 (s, 3H), 1.20-1.14 (m, 1H), 0.49-0.43 (m, 2H), 0.22-0.16 (m, 2H); LCMS C 25 H 34 N4S method (B) R t = 4.413 min, ESI+ m / z = 423.2 (M+H).

[0432] 1-Isopentyl-1-(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)thiourea OR0605-2 (92%), a pale yellow solid, was used in the next step without further purification. Rf=0.18 (DCM-MeOH-NH4OH, 90:9:1); LCMS C 26 H 38 N4S, Method (B)R t =4.820 min, ESI+m / z=439.3(M+H).

[0433] 1-Butyl-1-(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)thiourea OR0606-2 (63%) as a pale yellow solid. Rf=0.12 (DCM-MeOH, 95:5); 1 H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 7.9 Hz, 2H), 7.38 (d, J = 7.9 Hz, 1H), 7.33 (s, 1H), 7.29 (d, J = 7.9 Hz, 2H), 5.51 (brs, 2H), 4.50-4.47 (m, 1H), 3.69-3.67 (m, 1H), 2.87-2.85 (m, 2H), 2.69 (brs, 8H), 2.66-2.64 (m, 2H), 2.38 (s, 3H), 2.26 (s, 3H), 1.73-1.71 (m, 1H), 1.60-1.58 (m, 1H), 1.36-1.35 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 181.86, 140.93, 140.19, 140.04, 137.31, 134.50, 132.64, 129.51, 127.59, 126.98, 126.25, 60.11, 54.85, 54.82, 52.63, 45.72, 33.13, 29.66, 20.14, 17.15, 13.97; LCMS C 25 H 36 N4S method (B) R t = 4.593 min, ESI+ m / z = 425.3 (M+H).

[0434] 1-Isobutyl-1-(2-methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-3-yl)phenyl)thiourea OR0608-2 (90%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 2.5 Hz, 1H), 7.73 (dd, J = 8.6, 2.5 Hz, 1H), 7.47 (dd, J = 8.0, 1.9 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 1.9 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 5.49 (brs, 2H), 4.50 (t, J = 5.7 Hz, 2H), 3.39-3.31 (m, 2H), 2.92-2.84 (m, 2H), 2.81 (brs, 8H), 2.48 (s, 3H), 2.27 (s, 3H), 1.99-1.98 (m, 1H), 0.97 (d, J = 6.8 Hz, 6H); LCMS C 24 H 35 N5OS method (B) R t = 4.530 points, ESI+ m / z = 442.3 (M+H).

[0435] N-((1-(3-(1-イソブチルチオウレイド)-4-メチルフェニル)-1H-1,2,3-トリアゾール-4-イル)メチル)メタンスルホンアミドOR0609-2 (95%), white solid として. 1 H NMR (400 MHz, DMSO) δ 8.75 (s, 1H), 7.82-7.52 (m, 4H), 4.31 (s, 2H), 3.60 (brs, 2H), 2.95 (s, 3H), 2.18 (s, 3H), 1.90-1.78 (m, 1H), 0.96-0.86 (m, 6H); LCMS C 16 H 24 N6O2S2 method (B) R t = 5.127 points, ESI+ m / z = 397.2 (M+H).

[0436] tert-Butyl (2-(1-(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)thioureido)ethyl)carbamate OR0610-3 (98%) as a pale yellow solid, used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.53 (dd, J = 7.9, 1.4 Hz, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.40-7.36 (m, 2H), 7.26 (d, J = 8.1 Hz, 2H), 5.46 (brs, 1H), 4.80-4.72 (m, 1H), 3.86-3.78 (m, 1H), 3.54-3.38 (m, 2H), 2.89-2.81 (m, 2H), 2.72-2.64 (m, 2H), 2.63 (brs, 8H), 2.38 (s, 3H), 2.25 (s, 3H), 1.39 (s, 9H); LCMS C 28 H 41 N5O2S method (B) R t = 4.513 min, ESI+ m / z = 512.3 (M+H).

[0437] tert-Butyl (3-(1-(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)thioureido)propyl)carbamate OR0611-3 (90%) as a pale yellow solid, used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.53 (dd, J = 7.9, 1.8 Hz, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 1.8 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 5.56 (brs, 2H), 5.38 (brs, 1H), 4.74- 4.66 (m, 1H), 3.72-3.63 (m, 1H), 3.35-3.13 (m, 2H), 2.88-2.80 (m, 2H), 2.67-2.59 (m, 2H), 2.52 (brs, 8H), 2.31 (s, 3H), 2.25 (s, 3H), 1.94-1.71 (m, 2H), 1.42 (s, 9H); LCMS C 29 H 43 N5O2S method (B) R t = 4.607 min, ESI+ m / z = 526.3 (M+H).

[0438] 1-(2-methyl-5-(6-(4-methylpiperazine-1-carbonyl)pyridin-3-yl)phenyl)-1-propylthiourea OR0612-2 (82%) as a yellow solid. LCMS C 22 H 29 N5OS, Method (B)R t =4.215 min, ESI+m / z=412.2(M+H).

[0439] 4-Methyl-N-(5-(4-methyl-3-(1-propylthioureido)phenyl)pyridin-2-yl)piperazine-1-carboxamide OR0616-2 (88%) as a yellow solid. LCMS C 22 H 30 N6OS, Method (B)R t =4.309 min, ESI+m / z=427.3(M+H).

[0440] 1-(5-Fluoro-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)-1-propylthiourea OR0633-2 (97%) as a yellow solid. LCMS C 22 H 29 FN4O2S2, Method (B)R t =4.870 min, ESI+m / z=465.2(M+H).

[0441] General procedure for the synthesis of N-([1,1'-biaryl]-3-ylcarbamothioyl)benzamide derivatives. As previously described above.

[0442] N-((4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)(propyl)carbamothioyl)benzamide OR0600-3 (quantitative), a pale yellow solid, was used in the next step without further purification. LCMS C 31 H 38 N4OS, Method (B)R t =4.868 min, ESI+m / z=515.3(M+H).

[0443] N-(isobutyl(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)carbamothioyl)benzamide OR0603-3 (quantitative), as a white solid. LCMS C 32 H 40 N4OS, Method (B)R t =5.080 min, ESI+m / z=529.6(M+H).

[0444] N-((cyclopropylmethyl)(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)carbamothioyl)benzamide OR0604-3 (quantitative), as a white solid. LCMS C 32 H 38 N4OS, Method (B)R t =4.915 min, ESI+m / z=527.3(M+H).

[0445] N-(isopentyl(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)carbamothioyl)benzamide OR0605-3 (96%), a pale yellow solid, was used in the next step without further purification. Rf=0.40 (DCM-MeOH-NH4OH, 90:9:1); LCMS C 33 H 42 N4OS, Method (B)R t =5.154 min, ESI+m / z=543.3(M+H).

[0446] N-(butyl(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)carbamothioyl)benzamide OR0606-3 (96%), a pale yellow solid, was used in the next step without further purification. Rf=0.40 (DCM-MeOH-NH4OH, 90:9:1); LCMS C 32 H 40 N4OS, Method (B)R t =5.059 min, ESI+m / z=529.3(M+H).

[0447] N-(isobutyl(2-methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-3-yl)phenyl)carbamothioyl)benzamide OR0608-3 (quantitative) as a white solid. LCMS C 31 H 39 N5O2S, method (B)R t =5.074 min, ESI+m / z=546.3(M+H).

[0448] N-(isobutyl(2-methyl-5-(4-(methylsulfonamidomethyl)-1H-1,2,3-triazol-1-yl)phenyl)carbamothioyl)benzamide OR0609-3 (quantitative), as a white solid. LCMS C 23 H 28 N6O3S2, method (B)R t =5.882 min, ESI+m / z=501.2(M+H).

[0449] tert-Butyl (2-(3-benzoyl-1-(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)thioureido)ethyl)carbamate OR0610-4 (96%) as a pale yellow solid, used in the next step without further purification. LCMS C 35 H 45 N5O3S, method (B)R t =4.938 min, ESI+m / z=616.3(M+H).

[0450] tert-Butyl (3-(3-benzoyl-1-(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)thioureido)propyl)carbamate OR0611-4 (98%) as a pale yellow solid, used in the next step without further purification. LCMS C 36 H 47 N5O3S, method (B)R t =4.936 min, ESI+m / z=630.3(M+H).

[0451] N-((2-methyl-5-(6-(4-methylpiperazine-1-carbonyl)pyridin-3-yl)phenyl)(propyl)carbamothioyl)benzamide OR0612-3 (quantitative) as a beige solid. LCMS C 29 H 33 N5O2S, method (B)R t =4.773 min, ESI+m / z=516.3(M+H).

[0452] N-(5-(3-(3-benzoyl-1-propylthioureido)-4-methylphenyl)pyridin-2-yl)-4-methylpiperazine-1-carboxamide OR0616-3 (quantitative), as a yellow solid. LCMS C 29 H 34 N6O2S, method (B)R t =4.875 min, ESI+m / z=531.3(M+H).

[0453] N-((5-fluoro-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)carbamothioyl)benzamide OR0633-3 (quantitative), as a yellow solid. LCMS C 29 H 33 FN4O3S2, Method (B)R t =5.434 min, ESI+m / z=569.2(M+H).

[0454] General procedure for the synthesis of [1,1'-biaryl]-3-N-alkylamine derivatives. As previously described above.

[0455] N-Isobutyl-4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-amine OR0603-4 (75%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H), 7.10 (d, J = 7.7 Hz, 1H), 6.84 (dd, J = 7.7, 1.6 Hz, 1H), 6.77 (d, 2.17 (s, 3H), 2.02-1.92 (m, 1H), 1.02 (d, J = 6.7 Hz, 6H); LCMS C 24 H 35 N3 method (B) R t = 4.324 min, ESI+ m / z = 366.4 (M+H).

[0456] N-(cyclopropylmethyl)-4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-amine OR0604-4 (71%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 7.8 Hz, 1H), 6.86 (dd, J = 7.8, 1.6 Hz, 1H), 6.77 (d, J = 1.6 Hz, 1H), 3.06 (d, J = 6.9 Hz, 2H), 2.87-2.81 (m, 2H), 2.68-2.60 (m, 2H), 2.51 (brs, 8H), 2.31 (s, 3H), 2.20 (s, 3H), 1.20-1.14 (m, 1H), 0.61-0.55(m, 2H), 0.30-0.24 (m, 2H); LCMS C 24 H 33 N3 method (B) R t = 4.392 min, ESI+ m / z = 364.3 (M+H).

[0457] N-Isopentyl-4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-amine OR0605-4 (68%) as a pale yellow oil. Rf=0.45 (DCM-MeOH-NH4OH, 90:9:1); LCMS C 25 H 37 N3, Method (B)R t =4.966 min, ESI+m / z=380.6(M+H).

[0458] N-Butyl-4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-amine OR0606-4 (63%), used in the next step without further purification as a colorless oil. Rf=0.45 (DCM-MeOH-NH4OH, 90:9:1); LCMS C 24 H 35 N3, Method (B)R t =4.590 min, ESI+m / z=366.3(M+H).

[0459] N-Isobutyl-2-methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-3-yl)aniline OR0608-4 (44%) as a colorless oil. LCMS C 23 H 34 N4O, method (B)R t =4.859 min, ESI+m / z=383.3(M+H).

[0460] N-((1-(3-(isobutylamino)-4-methylphenyl)-1H-1,2,3-triazol-4-yl)methyl)methanesulfonamide OR0609-4 (68%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.32-7.28 (m, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.05-7.00 (m, 1H), 5.44 (brs, 1H), 4.55 (d, J = 5.4 LCMS C 15 H 23 N5O2S method (B) R t = 5.794 min, ESI+ m / z = 338.2 (M+H).

[0461] tert-Butyl (2-((4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)ethyl)carbamate OR0610-5 (35%) as a colorless oil. Rf=0.65 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 7.6 Hz, 1H), 6.85 (dd, J = 7.6, 1.2 Hz, 1H), 6.75 d, J = 1.2 Hz, 1H), 4.88 (brs, 1H), 4.18 (brs, 1H), 3.51-3.43 (m, 2H), 3.37-3.29 (m, 2H), 2.89-2.81 (m, 2H), 2.70-2.62 (m, 2H), 2.57 (brs, 8H), 2.35 (s, 3H), 2.17 (s, 3H), 1.45 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ 156.90, 146.39, 140.17, 139.99, 138.80, 130.42, 128.94, 127.16, 121.22, 115.69, 107.98, 79.68, 60.35, 54.96, 52.87, 45.86, 45.20, 40.01, 33.14, 28.39, 17.20; LCMS C 27 H 40 N4O2 method (B) R t = 4.851 min, ESI+ m / z = 453.4 (M+H).

[0462] tert-Butyl (3-((4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)propyl)carbamate OR0611-5 (46%) as a colorless oil. Rf=0.65 (DCM-MeOH-NH4OH, 90:9:1); 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 7.10 (d, J = 7.8 Hz, 1H), 6.85 (dd, J = 7.8, 1.6 Hz, 1H), 6.78 (d, J = 1.6 Hz, 1H), 4.70 (brs, 1H), 3.32-3.24 (m, 4H), 2.89-2.81 (m, 2H), 2.71-2.63 (m, 2H), 2.61 (brs, 8H), 2.36 (s, 3H), 2.18 (s, 3H), 1.84 (quintet, J = 6.6 Hz, 2H), 1.44 (s, 9H); LCMS C 28 H 42 N4O2 method (B) R t = 4.818 points, ESI+ m / z = 467.4 (M+H).

[0463] (5-(4-メチル-3-(プロピルアミノ)フェニル)ピリジン-2-イル)(4-メチルピペラジン-1-イル)メタノンOR0612-4 (95%), ベージュ-colored oily substance として. 1 H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 2.1 Hz, 1H), 7.97 (dd, J = 8.1, 2.1 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 6.85 (dd, J = 7.5, 1.8 Hz, 1H), 6.77 (d, J = 1.8 Hz, 1H), 3.89 (brs, 2H), 3.76 (brs, 2H), 3.20 (t, J = 7.1 Hz, 2H), 2.59 (brs, 2H), 2.51 (brs, 2H), 2.37 (s, 3H), 2.19 (s, 3H), 1.73 (sextet, J = 7.4 Hz, 2H), 1.05 (t, J = 7.4 Hz, 3H); LCMS C 21 H 28 N4O method (B) R t = 4.358 points, ESI+ m / z = 353.3 (M+H).

[0464] 4-Methyl-N-(5-(4-methyl-3-(propylamino)phenyl)pyridin-2-yl)piperazine-1-carboxamide OR0616-4 (90%) as a beige oil. 1 H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 2.2 Hz, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.87 (dd, J = 8.7, 2.2 Hz, 1H), 7.38 (brs, 1H), 7.11 (d, J = 7.7 Hz, 1H), 6.81 (dd, J = 7.7, 1.7 Hz, 1H), 6.73 (d, J = 1.7 Hz, 1H), 3.65-3.59 (m, 4H), 3.19 (t, J = 7.1 Hz, 2H), 2.57-2.53 (m, 4H), 2.39 (s, 3H), 2.17 (s, 3H), 1.72 (sextet, J = 7.4 Hz, 2H), 1.04 (t, J = 7.4 Hz, 3H); LCMS C 21 H 29 N5O method (B) R t = 4.217 min, ESI+ m / z = 368.3 (M+H).

[0465] 5-Fluoro-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-N-propyl-[1,1'-biphenyl]-3-amine OR0633-4 (55%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 8.5 Hz, 2H), 6.65 (dd, J = 10.2, 1.6 Hz, 1H), 6.55 (d, J = 1.6 Hz, 1H), 3.20 (t, J = 7.4 Hz, 2H), 3.19 (brs, 4H), 2.65 (brs, 4H), 2.38 (s, 3H), 2.08 (s, 3H), 1.72 (sextet, J = 7.4 Hz, 2H), 1.05 (t, J = 7.4 Hz, 3H); LCMS C 21 H 28 FN3O2S method (B) R t = 5.345 min, ESI+ m / z = 406.2 (M+H).

[0466] General procedure for the synthesis of [1,1'-biaryl]-3-amine derivatives. Method (A): A suspension of the appropriate 3-nitro-1,1'-biaryl (1 mmol), iron powder (280 mg, 5 mmol), and ammonium chloride (539 mg, 10 mmol) in a water-ethanol mixture (1:1, 20 mL) was refluxed until the reaction was complete, as indicated by TLC monitoring. The reaction mixture was filtered through a short Celite pad and rinsed with EtOH. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography to give the corresponding [1,1'-biaryl]-3-amine. Method (B): As previously described for 3-nitro-1,1'-biaryl derivatives starting from commercially available 3-amino-4-methylphenylboronic acid and the appropriate aryl halide.

[0467] 2-Methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-3-yl)aniline OR0608-5 (Method B, 85%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 2.5 Hz, 1H), 7.74 (dd, J = 8.6, 2.5 Hz, 1H), 7.11 (d, J = 7.7 Hz, 1H), 6.85 (dd, J = 7.7, 1.8 Hz, 1H), 6.82 (d, J = 1.8 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 4.48 (t, J = 5.8 Hz, 2H), 3.70 (brs, 2H), 2.84 (t, J = 5.8 Hz, 2H), 2.69 (brs, 4H), 2.58 (brs, 4H), 2.35 (s, 3H), 2.20 (s, 3H); LCMS C 19 H 26 N4O method (B) R t = 3.514 min, ESI+ m / z = 327.2 (M+H).

[0468] N-((1-(3-amino-4-methylphenyl)-1H-1,2,3-triazol-4-yl)methyl)methanesulfonamide OR0609-5 (Method A, 97%) as a pale yellow solid. LCMS C 11 H 15 N5O2S, method (B)R t =4.179 min, ESI+m / z=282.2(M+H).

[0469] (5-(3-amino-4-methylphenyl)pyridin-2-yl)(4-methylpiperazin-1-yl)methanone OR0612-5 (Method B, 90%) as a beige solid. 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 7.92 (dd, J = 8.1, 1.9 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.15 (d, J = 7.7 Hz, 1H), 6.91 (d, J = 7.7 Hz, LCMS C 18 H 22 N4O method (B) R t = 2.725 min, ESI+ m / z = 311.2 (M+H).

[0470] N-(5-(3-amino-4-methylphenyl)pyridin-2-yl)-4-methylpiperazine-1-carboxamide OR0616-5 (Method B, 70%) as an orange solid. 1 H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 2.2 Hz, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.83 (dd, J = 8.7, 2.2 Hz, 1H), 7.43 (brs, 1H), 7.11 (d, J = 7.7 Hz, 1H), 6.88 (dd, J = 7.7, 1.7 Hz, 1H), 6.85 (d, J = 1.7 Hz, 1H), 3.62-3.57 (m, 4H), 2.53-2.47 (m, 4H), 2.36 (s, 3H), 2.20 (s, 3H); LCMS C 18 H 23 N5O method (B) R t = 2.298 min, ESI+ m / z = 326.1 (M+H).

[0471] 5-Fluoro-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-amine OR0633-5 (Method A, quantitative) as a yellow oil. LCMS C 18H 22 FN3O2S, method (B)R t =4.657 min, ESI+m / z=364.1(M+H).

[0472] 1-(2-((5-bromopyridin-2-yl)oxy)ethyl)-4-methylpiperazine OR0608-6 i From commercially available 5-bromo-2-fluoropyridine and 2-(4-methylpiperazin-1-yl)ethan-1-ol (62%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 2.5 Hz, 1H), 7.62 (dd, J = 8.8, 2.5 Hz, 1H), 6.66 (d, J = 8.8 Hz, 1H), 4.40 (t, J = 5.8 Hz, 2H), 2.78 (t, J = 5.8Hz, 2H), 2.63 (brs, 4H), 2.52 (brs, 4H), 2.31 (s, 3H); LCMS C 12 H 18 BrN3O method (B) R t = 3.571 min, ESI+ m / z = 300.0 (M+H).

[0473] N-((1-(4-methyl-3-nitrophenyl)-1H-1,2,3-triazol-4-yl)methyl)methanesulfonamide OR0609-6 To a mixture of N-(prop-2-yn-1-yl)methanesulfonamide (620 mg, 4.66 mmol), CuSO pentahydrate (30 mg, 0.12 mmol), and sodium ascorbate (118 mg, 0.60 mmol) in a mixture of tert-butanol and HO (1:1, 30 mL) was added 4-azido-1-methyl-2-nitrobenzene. ii(817 mg, 4.59 mmol) was added. The suspension was stirred at room temperature for 48 hours until the starting material was consumed as monitored by LCMS. The solvent was evaporated under reduced pressure, and the residue was dissolved in 10% aqueous NH4OH (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography, gradient DCM-EtOAc (100:0 to 65:35) to give N-((1-(4-methyl-3-nitrophenyl)-1H-1,2,3-triazol-4-yl)methyl)methanesulfonamide OR0609-6 (1.24 g, 87%) as a beige solid. 1 H NMR (400 MHz, DMSO) δ 8.87 (s, 1H), 8.53 (d, J = 2.3 Hz, 1H), 8.20 (dd, J = 8.3, 2.3 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.64 (s, 1H), 4.33 (s, 2H), 2.96 (s, 3H), 2.57 (s, 3H); LCMS C 11 H 13 N5O4S method (B) R t = 5.027 min, ESI+ m / z = 312.1 (M+H).

[0474] N-(5-bromopyridin-2-yl)-4-methylpiperazine-1-carboxamide OR0616-6 4-Nitrophenyl (5-bromopyridin-2-yl)carbamate from OR0616-7 (79%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 8.23 ​​(d, J = 2.4 Hz, 1H), 7.96 (d, J = 8.9 Hz, 1H), 7.73 (dd, J = 8.9, 2.4 Hz, 1H), 3.61-3.54 (m, 4H), 2.54-2.47 (m, 4H), 2.36 (s, 3H).

[0475] 4-Nitrophenyl(5-bromopyridin-2-yl)carbamate OR0616-7 iii From commercially available 5-bromopyridin-2-amine and 4-nitrophenyl chloroformate (43%) as a white powder. LCMS C 12 H8BrN3O4, method (B)R t =6.490 min, ESI+m / z=338.0(M+H).

[0476] 1-((3'-Fluoro-4'-methyl-5'-nitro-[1,1'-biphenyl]-4-yl)sulfonyl)-4-methylpiperazine OR0633-6 As previously described for 3-nitro-1,1'-biaryl derivatives, from commercially available 5-bromo-1-fluoro-2-methyl-3-nitrobenzene and 1-methyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)piperazine (quantitative) as a yellow oil. LCMS C 18 H 20 FN3O4S, Method (B)R t =5.007 min, ESI+m / z=394.2(M+H).

[0477] General procedure for the synthesis of 4,4,5,5-tetramethyl-2-aryl-1,3,2-dioxaborolanes. Method (A): Under argon, a suspension of the appropriate aryl halide (5.6 mmol), bis(pinacolato)diboron (3.63 g, 14.3 mmol), potassium acetate (2.80 g, 28.6 mmol), and PdCl(dppf) (697 mg, 0.9 mmol) in degassed 1,4-dioxane (50 mL) was refluxed for 2 h, after which the starting material was completely consumed. The resulting mixture was subsequently cooled to room temperature, filtered through a short Celite pad, and washed with EtOAc. The solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography to give the corresponding 4,4,5,5-tetramethyl-2-aryl-1,3,2-dioxaborolanes. Method (B): Under argon, to a solution of the appropriate aryl halide (1.0 mmol) in tetrahydrofuran (5 mL) at −78° C. was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.37 mL, 1.8 mmol) followed by n-BuLi (2.5 M in hexanes, 0.47 mL, 1.18 mmol) over 5 min. After the addition, the resulting mixture was stirred at −78° C. for 30 min and then quenched with water (5 mL). The aqueous layer was successively washed with DCM (3 × 5 mL), acidified to pH = 7 with 2 M aqueous HCl, and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over NaSO, and the solvent was evaporated under reduced pressure to give the expected 4,4,5,5-tetramethyl-2-aryl-1,3,2-dioxaborolane.

[0478] Ethyl 2-((2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(propyl)amino)thiazole-4-carboxylate OR0625-2 (Method A, quantitative), as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.73 (dd, J = 7.5, 1.2 Hz, 1H), 7.62 (d, J = 1.2 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.26 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H), 4.02-3.75 (m, 2H), 2.24 (s, 3H), 1.67 (sextet, J = 7.4 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 1.34 (s, 12H), 0.92 (t, J = 7.4 Hz, 3H); LCMS C 22 H 31 BN2O4S method (B) R t = 6.109 min, ESI+ m / z = 349.2 (ArB(OH)2+H).

[0479] 1-Methyl-4-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)sulfonyl)piperazine OR0627-2 (Method B, 43%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 9.00 (d, J = 1.7 Hz, 1H), 8.26 (dd, J = 7.7, 1.7 Hz, 1H), 7.88 (d, J = 7.7 Hz, 1H), 3.50 (brs, 4H), 2.71 (brs, 4H), 2.45 (s, 3H), 1.36 (s, 12H); LCMS C 16 H 26 BN3O4S method (B) R t = 1.149 min, ESI+ m / z = 286.1 (ArB(OH)2+H).

[0480] 1-Methyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)phenyl)sulfonyl)piperazine OR0642-2 (Method A, 83%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.87 (dd, J = 7.8, 1.4 Hz, 1H), 3.17 (brs, 4H), 2.63 (brs, 4H), 2.38 (s, 3H), 1.38 (s, 12H); LCMS C 18 H 26 BF3N2O4S method (B) R t = 4.951 min, ESI+ m / z = 435.2 (M+H).

[0481] (4-Methyl-6-((4-methylpiperazin-1-yl)sulfonyl)pyridin-3-yl)boronic acid OR0652-2 (Method B), the aqueous layer was acidified to pH=3. The aqueous layer was washed with DCM (3×50 mL) and then concentrated under reduced pressure to give (4-methyl-6-((4-methylpiperazin-1-yl)sulfonyl)pyridin-3-yl)boronic acid OR0652-2 (40%) as a white solid. LCMS C 11 H 18 BN3O4S, Method (B)R t =1.542 min, ESI+m / z=300.2(M+H).

[0482] General procedure for the synthesis of 1-(4-halogeno-benzenesulfonyl)-4-methyl-piperazine derivatives. Under argon, 1-methyl-piperazine (125 μL, 1.12 mmol) was added to a solution of the appropriate 4-halogenobenzenesulfonyl chloride (1.0 mmol) in dichloromethane (6 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes and allowed to warm to room temperature. After stirring for 2 hours, the mixture was diluted with DCM (15 mL), and then saturated aqueous NaCO solution (5 mL) was added, and the aqueous layer was extracted with DCM (2×15 mL). The combined organic layers were dried over NaSO, and the solvent was evaporated under reduced pressure to give the corresponding 1-(4-halogeno-benzenesulfonyl)-4-methyl-piperazine, which was used in the next step without further purification.

[0483] 1-((5-Bromopyridin-2-yl)sulfonyl)-4-methylpiperazine OR0627-3 (quantitative). 1 H NMR (400 MHz, CDCl3) δ 8.73 (d, J = 2.0 Hz, 1H), 8.03 (dd, J = 8.3, 2.0 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 3.38-3.30 (m, 4H), 2.52-2.44 (m, 4H), 2.29 (s, 3H); LCMS C 10 H 14 BrN3O2S method (B) R t = 3.703 min, ESI+ m / z = 320.0 (M+H).

[0484] 1-((4-Bromo-3-(trifluoromethyl)phenyl)sulfonyl)-4-methylpiperazine OR0642-3 (99%). 1 H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 1.9 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.74 (dd, J = 8.3, 2.0 Hz, 1H), 3.12-3.04 (m, 4H), 2.56-2.48 (m, 4H), 2.29 (s, 3H); LCMS C 10 H 14 BrN3O2S method (B) R t = 4.419 min, ESI+ m / z = 387.0 (M+H).

[0485] 1-((5-Bromo-4-methylpyridin-2-yl)sulfonyl)-4-methylpiperazine OR0652-3 (63%) as a white solid. 1 LCMS C 11 H 16 BrN3O2S method (B) R t= 4.075 min, ESI+ m / z = 334.0 (M+H).

[0486] N-(5-bromopyridin-2-yl)-4-methylpiperazine-1-sulfonamide OR0625-4 A modified procedure described by Borghese et al. iv A mixture of N-(5-bromopyridin-2-yl)-2-oxooxazolidine-3-sulfonamide OR0625-5 (1.73 g, 5.37 mmol), 1-methylpiperazine (600 μL, 5.37 mmol), and triethylamine (2.25 mL, 16.13 mmol) in acetonitrile (27 mL) was refluxed for 4 days using HCl. After complete consumption of the starting material (monitored by LCMS), the solvent was evaporated under reduced pressure, and saturated aqueous NaHCO was added until pH = 8. The aqueous layer was then extracted with DCM (3 × 40 mL). The combined organic layers were dried over NaSO, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography, gradient DCM-MeOH-NH4OH (100:0:0 to 90:9:1) to afford N-(5-bromopyridin-2-yl)-4-methylpiperazine-1-sulfonamide OR0625-4 (311 mg, 17%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 2.4 Hz, 1H), 7.78 (dd, J = 8.9, 2.4 Hz, 1H), 7.28 (d, J = 8.9 Hz, 1H), 3.39-3.32 (m, 4H), 2.55-2.48 (m, 4H), 2.33 (s, 3H); LCMS C 10 H 15 BrN4O2S method (B) R t = 3.567 min, ESI+ m / z = 335.0 (M+H).

[0487] N-(5-bromopyridin-2-yl)-2-oxooxazolidine-3-sulfonamide OR0625-5 A modified procedure described by Borghese et al. ivTo a solution of chlorosulfonyl isocyanate (503 μL, 5.78 mmol) in dry dichloromethane (20 mL) at 0° C. under argon, 2-chloroethan-1-ol (390 μL, 5.78 mmol) was added dropwise using a PBS. After stirring at 0° C. for 1 hour, triethylamine (2.5 mL, 17.30 mmol) was added, followed by the dropwise addition of a solution of 5-bromopyridin-2-amine (1.0 g, 5.78 mmol) in dry dichloromethane (15 mL). The resulting mixture was stirred at 0° C. for an additional hour, then warmed to room temperature and stirred overnight. The reaction was quenched by the addition of 0.25 N aqueous HCl, extracted with DCM (2×40 mL), and the combined organic layers were dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure and the crude residue was triturated with cyclohexane to give N-(5-bromopyridin-2-yl)-2-oxooxazolidine-3-sulfonamide OR0625-5 (1.73 g, 93%) as a white solid. LCMS C8H8BrN3O4S, Method (B)R t =4.761 min, ESI+m / z=322.0(M+H).

[0488] 2-((5-bromopyridin-2-yl)oxy)-1-(4-methylpiperazin-1-yl)ethan-1-one OR0630-2 by peptide coupling from commercially available 2-((5-bromopyridin-2-yl)oxy)acetic acid using a procedure identical to that described for the di-tert-butyl (2-(2-((3-benzamidoaryl)amino)thiazol-4-yl)pyrimidin-4-yl)carbamate derivative. 1 H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 2.4 Hz, 1H), 7.67 (dd, J = 8.8, 2.4 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 4.97 (s, 2H), 3.67 (brs, 2H), 3.53 (brs, 2H), 2.48 (brs, 2H), 2.45 (brs, 2H), 2.34 (s, 3H); LCMS C 12 H 16 BrN3O2 method (B) R t= 3.649 min, ESI+ m / z = 314.0 (M+H).

[0489] General procedure for the synthesis of ethyl 2-((5-halogeno-2-methylphenyl)amino)thiazole-4-carboxylate derivatives and analogs. Method (A): Synthesis of ethyl 2-([1,1'-biaryl]-3-ylamino)thiazole-4-carboxylate derivatives, as previously described for Method (A). Method (B): To a suspension of ethyl 2-((5-halogeno-2-methylphenyl)amino)thiazole-4-carboxylate or analog (0.16 mol) and cesium carbonate (73 g, 0.22 mol) in dimethylformamide (1 L) was added the appropriate alkyl halide (20 mL, 0.22 mol). The reaction mixture was stirred at rt for 72 h until the starting material was completely consumed. The solvent was evaporated under reduced pressure, and the residue was poured onto water (300 mL) and extracted with EtO (3 x 300 mL). The combined organic layers were dried over NaSO and concentrated in vacuo. The residue was purified by flash chromatography to give the corresponding ethyl 2-((5-halogeno-2-methylphenyl)(alkyl)amino)thiazole-4-carboxylate or analog.

[0490] Ethyl 2-((5-iodo-2-methylphenyl)(propyl)amino)thiazole-4-carboxylate OR0607-2 (Method A, 73%) as a pale yellow solid. Rf=0.20 (DCM-PE, 80:20); 1 H NMR (400 MHz, CDCl3) δ 7.62 (dd, J = 8.1, 1.8 Hz, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.30 (s, 1H), 7.08 (d, J = 8.1 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.88 (brs, 2H), 2.17 (s, 3H), 1.64 (sextet, J = 7.4 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.27, 161.88, 144.08, 143.88, 138.22, 137.96, 137.26, 133.88, 116.96, 91.05, 61.20, 53.96, 21.11, 17.42, 14.47, 11.37; LCMS C 16 H 19 IN2O2S method (B) R t = 8.676 points, ESI+ m / z = 431.0 (M+H).

[0491] エチル2-(((5-ブロモ-2-メチルフェニル)(プロピル)アミノ)チアゾール-4-Korrotech OR0625-3 (method B, 54%), thin brown solid として. Rf=0.31(DCM); 1 H NMR (400 MHz, CDCl3) δ 7.44 (dd, J = 8.2, 2.0 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.31 (s, 1H), 7.22 (d, J = 8.2 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.89 (brs, 2H), 2.17 (s, 3H), 1.64 (sextet, J = 7.4 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.27, 161.90, 143.95, 143.90, 136.50, 133.63, 132.39, 132.06, 120.22, 117.00, 61.22, 53.95, 21.13, 17.34, 14.47, 11.37; LCMS C 16 H 19 BrN2O2S method (B) R t = 7.376 points, ESI+ m / z = 383.0 (M+H).

[0492] Ethyl 2-((5-bromo-2-methylphenyl)(methyl)amino)thiazole-4-carboxylate OR0631-2 (Method B, 37%) as a light brown solid. Rf=0.29 (DCM); 1 H NMR (400 MHz, CDCl3) δ 7.43 (dd, J = 8.2, 2.0 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.35 (s, 1H), 7.22 (d, J = 8.2 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.50 (s, 3H), 2.18 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.17, 161.80, 145.38, 143.87, 135.77, 133.61, 132.13, 131.39, 120.39, 117.47, 61.34, 40.01, 27.04, 17.17, 14.48; LCMS C 14 H 15 BrN2O2S method (B) R t = 7.212 min, ESI+ m / z = 355.0 (M+H).

[0493] Ethyl 2-((5-bromo-2-methylphenyl)(ethyl)amino)thiazole-4-carboxylate OR0632-2 (Method B, 41%) as a light brown solid. Rf=0.29 (DCM); 1 H NMR (400 MHz, CDCl3) δ 7.44 (dd, J = 8.2, 2.0 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.31 (s, 1H), 7.23 (d, J = 8.2 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 4.01 (brs, 2H), 2.18 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.00, 161.96, 144.01, 143.57, 136.65, 133.57, 132.52, 132.09, 120.23, 117.05, 61.21, 46.91, 17.33, 14.49, 13.12; LCMS C 15 H 17 BrN2O2S method (B) R t = 7.570 min, ESI+ m / z = 369.0 (M+H).

[0494] Ethyl 2-((5-bromo-2-methylphenyl)(isopropyl)amino)thiazole-4-carboxylate OR0636-2 (Method B, 67%) as a pale yellow solid. Rf=0.34 (DCM); 1 H NMR (400 MHz, CDCl3) δ 7.47 (dd, J = 8.2, 2.1 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 7.28 (s, 1H), 7.24 (d, J = 8.2 Hz, 1H), 5.07 (septet, J = 6.7 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 2.18 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H), 1.25-1.23 (m, 6H); 13 C NMR (100 MHz, CDCl3) δ 169.99, 161.99, 143.95, 141.33, 138.00, 133.75, 133.56, 132.32, 119.97, 116.64, 61.14, 52.25, 20.76, 17.83, 14.49; LCMS C 16 H 19 BrN2O2S method (B) R t = 7.818 min, ESI+ m / z = 383.0 (M+H).

[0495] Ethyl 2-((5-bromo-2-methylphenyl)(isobutyl)amino)thiazole-4-carboxylate OR637-2 (Method B, 60%) as a pale yellow solid. Rf=0.34 (DCM); 1H NMR (400 MHz, CDCl3) δ 7.43 (dd, J = 8.2, 2.0 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.30 (s, 1H), 7.22 (d, J = 8.2 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.73 (brs, 2H), 2.17 (s, 3H), 2.05-1.92 (m, 1H), 1.36 (t, J = 7.1 Hz, 3H), 0.98 (d, J = 6.7 Hz, 6H); 13 C NMR (100 MHz, CDCl3) δ 170.81, 161.85, 144.52, 143.86, 136.21, 133.84, 132.28, 131.96, 120.14, 117.00, 61.16, 59.87, 27.50, 20.51, 17.50, 14.46; LCMS C 17 H 21 BrN2O2S method (B) R t = 7.806 points, ESI+ m / z = 397.0 (M+H).

[0496] エチル2-((5-ブロモ-2-メチルフェニル)(プロピル)アミノ)オキサゾール-4-カルボキシレートOR0640-2 (method B, 60%), yellow oily substance. 1 H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.38 (dd, J = 8.2, 2.0 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.81-3.73 (m, 2H), 2.12 (s, 3H), 1.66 (sextet, J = 7.4 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H); LCMS C 16 H 19 BrN2O3 method (B) R t = 7.253 points, ESI+ m / z = 367.0 (M+H).

[0497] Ethyl 2-((5-bromo-2-methylphenyl)amino)thiazole-4-carboxylate OR0614-2 (Method A, quantitative), used in the next step without further purification as a yellow solid, Rf=0.50 (PE-EtOAc, 70:30); 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 2.0 Hz, 1H), 7.49 (s, 1H), 7.23 (dd, J = 8.1, 2.0 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 2.23 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 166.65, 161.45, 143.18, 139.75, 132.67, 129.64, 128.43, 124.36, 120.19, 117.02, 61.46, 17.59, 14.45; LCMS C 13 H 13 BrN2O2S method (B) R t = 6.664 min, ESI+ m / z = 341.0 (M+H).

[0498] Ethyl 2-((5-bromo-2-methylphenyl)amino)oxazole-4-carboxylate OR0640-3 (Method A, 21%) as a white solid. LCMS C 13 H 13 BrN2O3, method (B)R t =6.396 min, ESI+m / z=325.0(M+H).

[0499] General procedure for the synthesis of 1-(5-halogeno-2-methylphenyl)thiourea derivatives. As previously described for the synthesis of 1-(3-nitroaryl)thioureas.

[0500] 1-(5-iodo-2-methylphenyl)-1-propylthiourea OR0607-3 (98%) as a yellow solid was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.62 (dd, J = 8.1, 1.7 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 5.51 (brs, 2H), 4.38-.30 (m, LCMS C 11 H 15 IN2S method (B) R t = 6.324 min, ESI+ m / z = 335.0 (M+H).

[0501] 1-(5-bromo-2-methylphenyl)thiourea OR0614-3 (71%) as a yellow solid. Rf=0.18 (PE-EtOAc, 70:30); 1 H NMR (400 MHz, MeOD) δ 7.42 (d, J = 1.9 Hz, 1H), 7.38 (dd, J = 8.2, 2.0 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 2.23 (s, 3H); LCMS C8H9BrN2S method (B) R t = 4.773 min, ESI+ m / z = 245.0 (M+H).

[0502] 1-(5-Bromo-2-methylphenyl)urea OR0640-4 To a solution of 5-bromo-2-methylaniline (2.0 g, 10.75 mmol) in glacial acetic acid (22 mL) was added potassium cyanate (1.75 g, 21.5 mmol) in portions. The reaction mixture was stirred at rt for 2 h, after which the starting material was completely consumed as monitored by LCMS. The resulting suspension was diluted with water (200 mL), and the precipitate was collected by filtration to give 1-(5-bromo-2-methylphenyl)urea OR0640-4 (2.46 g, quantitative) as a beige solid, which was used in the next step without further purification. LCMS C8H9BrNO, Method (B)R t =4.833 min, ESI+m / z=229.0(M+H).

[0503] General procedure for the synthesis of N-((5-halogeno-2-methylphenyl)carbamoth...

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, Y and Z independently represent NH, N, O, or S; R 1 , R 2 and R 3 are independently hydrogen, -NR 7 R 8 Group(R 7 and R 8 are independently hydrogen or (C 1 ~C 6 ) an alkyl group) and halogen; R 4 and R 5 are independently hydrogen, cycloalkyl, and -NR 9 R 10 Group(R 9 and R 10 are independently hydrogen or (C 1 ~C 6 ) alkyl group) 1 ~C 6 ) represents an alkyl group, or R 4 and R 5 together to form azepanil, R 6 represents hydrogen or halogen; X 1 is an -NHCO- group, an oxygen atom, a halogen, a -C≡C- group or an -O-CH 2 represents a - group, X 2 is optionally substituted with at least one halogen (C 1 ~C 6 ) alkyl groups, optionally substituted with at least one halogen (C 1 ~C 6 ) represents a 5- to 12-membered ring optionally substituted with at least one group selected from the group consisting of alkoxy groups, halogen, and hydroxy; X 3 teeth, - substituted with at least one A group (C 1 ~C 6 ) alkyl, - substituted with at least one A group (C 1 ~C 6 ) alkoxy, -C(O)- substituted by at least one A group, -SO substituted with at least one A group 2 -, -NH-SO substituted with at least one A group 2 -, -NHCO- substituted by at least one A group, wherein at least one of said A groups is - (C 1 ~C 6 ) substituted by alkyl or by —COOH (C 1 ~C 6 ) piperazinyl optionally substituted with alkyl; - (C 1 ~C 6 ) -CO-piperazinyl substituted by alkyl, - morpholinyl, -NR 7 R 8 Group(R 7 and R 8 are independently hydrogen or (C 1 ~C 6 ) piperidinyl optionally substituted with ) an alkyl group; - (C 1 ~C 6 ) 2,6-diazaspiro[3.3]heptanyl substituted by alkyl; -NR 11 R 12 Group(R 11 and R 12 are independently hydrogen, (C 1 ~C 6 ) alkyl group or -SO 2 -CH 3 (which is the base), - -NH-(C 1 ~C 6 )Alkyl-NR 13 R 14 Group(R 13 and R 14 are independently hydrogen or (C 1 ~C 6 ) alkyl group, - (C 1 ~C 6 ) alkoxy, and - Hydroxy selected from the group consisting of Hydroxy, and -NR 15 R 16 Group(R 15 and R 16 are independently hydrogen or (C 1 ~C 6 ) alkyl group) represents a group selected from the group consisting of n 1 , n 2 and n 3 are independently 0 or 1) and pharmaceutically acceptable salts, tautomers and solvates thereof.

2. Y and Z independently represent NH, N, O, or S; R 1 , R 2 and R 3 are independently hydrogen, -NR 7 R 8 Group(R 7 and R 8 are independently hydrogen or (C 1 ~C 6 ) an alkyl group) and halogen; R 4 and R 5 are independently hydrogen, cycloalkyl, and —NR 9 R 10 Group(R 9 and R 10 are independently hydrogen or (C 1 ~C 6 ) alkyl group) 1 ~C 6 ) represents an alkyl group, or R 4 and R 5 together to form azepanil, R 6 represents hydrogen or halogen; X 1 is an -NHCO- group, an oxygen atom, a -C≡C- group or an -O-CH 2 represents a - group, X 2 is optionally substituted with at least one halogen (C 1 ~C 6 ) alkyl groups, optionally substituted with at least one halogen (C 1 ~C 6 ) represents a 5- to 12-membered ring optionally substituted with at least one group selected from the group consisting of alkoxy groups and halogens; X 3 but, - substituted with at least one A group (C 1 ~C 6 ) alkyl, - substituted with at least one A group (C 1 ~C 6 ) alkoxy, -C(O)- substituted by at least one A group, -SO substituted with at least one A group 2 -, -NH-SO substituted with at least one A group 2 -, -NHCO- substituted by at least one A group, wherein at least one of said A groups is - (C 1 ~C 6 ) substituted by alkyl or by —COOH (C 1 ~C 6 ) piperazinyl optionally substituted with alkyl; - (C 1 ~C 6 ) -CO-piperazinyl substituted by alkyl, - morpholinyl, -NR 7 R 8 Group(R 7 and R 8 are independently hydrogen or (C 1 ~C 6 ) piperidinyl optionally substituted with ) an alkyl group; - (C 1 ~C 6 ) 2,6-diazaspiro[3.3]heptanyl substituted by alkyl; -NR 11 R 12 Group(R 11 and R 12 are independently hydrogen, (C 1 ~C 6 ) alkyl group or -SO 2 -CH 3 (which is the base), - -NH-(C 1 ~C 6 )Alkyl-NR 13 R 14 Group(R 13 and R 14 are independently hydrogen or (C 1 ~C 6 ) alkyl group, - (C 1 ~C 6 ) alkoxy, and - Hydroxy selected from the group consisting of Hydroxy, and -NR 15 R 16 Group(R 15 and R 16 are independently hydrogen or (C 1 ~C 6 ) alkyl group) represents a group selected from the group consisting of n 1 , n 2 and n 3 The compound of claim 1, wherein is independently 0 or 1.

3. The compound is represented by the following formula (I'): 【Chemistry 2】 (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 2 , X 3 , n 1 , n 2 and n 3 is as defined in claim 1) 2. The compound of claim 1, having the formula:

4. R 1 , R 2 and R 3 10. The compound of claim 1, wherein at least one group selected from: is not hydrogen.

5. R 1 But, -NR 7 R 8 Group(R 7 and R 8 is hydrogen), R 2 represents hydrogen or halogen, preferably hydrogen, R 3 is hydrogen or -NR 7 R 8 Group(R 7 and R 8 is hydrogen), preferably —NR 7 R 8 Group(R 7 and R 8 is hydrogen.

6. R 4 is hydrogen or cycloalkyl, or -NR 9 R 10 Group(R 9 and R 10 is hydrogen) 1 ~C 6 ) alkyl group, preferably R 4 However, (C 1 ~C 6 ) represents an alkyl group, R 5 However, (C 1 ~C 6 ) represents an alkyl group, preferably a methyl group.

7. n 1 +n 2 +n 3 is equal to or greater than 1, preferably n 1 +n 2 +n 3 The compound of claim 1, wherein is 1, 2 or 3.

8. n 1 2. The compound of claim 1, wherein

9. n 1 is 1 and X 1 2. The compound of claim 1, wherein represents a -NHCO- group.

10. n 2 is 1 and X 2 represents a 5- to 12-membered ring selected from the group consisting of phenyl, pyrimidinyl, thiophenyl, pyridinyl, triazolyl, and indolyl, wherein said 5- to 12-membered ring is optionally substituted with at least one group selected from the group consisting of methoxy, trifluoromethoxy, halogen, hydroxy, methyl, and trifluoromethyl.

11. n 3 is 1 and X 3 However, (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) Alkoxy, -C(O)-, -SO 2 -, -NH-SO 2 - and -NHCO-, wherein the group is (C 1 ~C 6 ) The compound according to claim 1, which is substituted by piperazinyl optionally substituted by alkyl, preferably piperazinyl substituted by methyl.

12. n 3 is 1 and X 3 is substituted by at least one A group as defined in claim 1, preferably methyl, piperazinyl, -N(CH 3 ) 2 , 2,6-diazaspiro[3.3]heptanyl substituted by methyl and -NHSO 2 CH 3 is replaced by (C 1 ~C 6 ) alkyl.

13. n 3 is 1 and X 3 is substituted by at least one A group as defined in claim 1, preferably methyl, piperazinyl, -NR 11 R 12 Group(R 11 and R 12 are independently hydrogen or a methyl group) and morpholinyl substituted with —SO 2 2. The compound of claim 1, wherein

14. R 1 , R 2 and R 3 are independently hydrogen or -NR 7 R 8 Group(R 7 and R 8 are independently hydrogen), and preferably R 1 and R 3 NH 2 represents R 2 represents H, R 4 and R 5 However, independently, (C 1 ~C 6 ) alkyl group, preferably R 4 represents propyl, and R 5 represents methyl, R 6 represents hydrogen, X 2 represents a 5- to 6-membered ring selected from the group consisting of phenyl and pyridinyl, said 5- to 6-membered ring being optionally substituted with at least one group selected from the group consisting of trifluoromethyl, trifluoromethoxy, halogen, hydroxy, methoxy, and methyl; X 3 However, (C 1 ~C 6 ) substituted by alkyl or by —COOH (C 1 ~C 6 ) piperazinyl optionally substituted with alkyl, -NH 2 piperidinyl optionally substituted by -NH-(C 1 ~C 6 )Alkyl-NH 2 -SO substituted with at least one group selected from the group consisting of 2 - represents n 1 is 0, n 2 and n 3 2. The compound of claim 1, wherein

15. The compound is - N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide dCKi-1; - N-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide dCKi-2: - N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide OR0105; - N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)-2-((4-methylpiperazin-1-yl)methyl)pyrimidine-5-carboxamide OR0125; - 4-(4-aminopyrimidin-2-yl)-N-(2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)phenoxy)phenyl)thiazol-2-amine OR0143; - N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-4-(2-(4-methylpiperazin-1-yl)ethyl)benzamide OR0146; - 4-(4-aminopyrimidin-2-yl)-N-(2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)phenyl)ethynyl)phenyl)thiazol-2-amine OR0153; - N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-4-((dimethylamino)methyl)benzamide OR0155; - N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-4-((6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl)benzamide OR0156; - 4-(4-aminopyrimidin-2-yl)-N-(2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)benzyloxy)phenyl)thiazol-2-amine OR0232; - 4-(4-aminopyrimidin-2-yl)-N-(5-((4-((dimethylamino)methyl)phenyl)ethynyl)-2-methylphenyl)thiazol-2-amine OR0237; - N-(3-((4-(4-amino-5-fluoropyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide OR0239; - N-(3-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4-methylphenyl)-5-((4-methylpiperazin-1-yl)methyl)thiophene-2-carboxamide OR0241; - 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-3-yl)thiazol-2-amine OR0274; - N-(1-(4-(4-aminopyrimidin-2-yl)thiazol-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide OR0289; - 3'-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4'-methyl-[1,1'-biphenyl]-4-ol OR0320; - 3'-((4-(4-aminopyrimidin-2-yl)thiazol-2-yl)amino)-4'-methyl-[1,1'-biphenyl]-4-ol OR0321; - 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)thiazol-2-amine OR0325; - 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-(3-(4-methylpiperazin-1-yl)propyl)-[1,1'-biphenyl]-3-yl)thiazol-2-amine OR0331; - 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-(3-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)-N-propylthiazol-2-amine OR0345; - 2-(2-(8-(4-(2-(4-methylpiperazin-1-yl)ethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)thiazol-4-yl)pyrimidin-4-amine OR0402; - 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethoxy)-[1,1'-biphenyl]-3-yl)-N-propylthiazol-2-amine OR0596; - 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy)-[1,1'-biphenyl]-3-yl)-N-propylthiazol-2-amine OR0597; - 4-(4-aminopyrimidin-2-yl)-N-(4-methyl-4'-(3-(4-methylpiperazin-1-yl)propyl)-[1,1'-biphenyl]-3-yl)-N-propylthiazol-2-amine OR0598; - 4-(4-aminopyrimidin-2-yl)-N-(2-methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethyl)pyridin-3-yl)phenyl)-N-propylthiazol-2-amine OR0599; - 2-(2-((4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0600; - 2-(2-((4-methyl-4'-(3-(4-methylpiperazin-1-yl)propyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0601; - 2-(2-((2-methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0602; - 2-(2-(iso-butyl(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0603; - 2-(2-((cyclopropylmethyl)(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0604; - 2-(2-(iso-pentyl(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0605; - 2-(2-(butyl(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0606; - 2-(2-((4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0607; - 2-(2-(iso-butyl(2-methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-3-yl)phenyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0608; - N-((1-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(isobutyl)amino)-4-methylphenyl)-1H-1,2,3-triazol-4-yl)methyl)methanesulfonamide OR0609; - 2-(2-((2-aminoethyl)(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0610; - 2-(2-((3-aminopropyl)(4-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0611; - 2-[2-({2-methyl-5-[6-(4-methyl-piperazin-1-ylcarbonyl)-pyridin-3-yl]-phenyl}-propyl-amino)-thiazol-4-yl]-pyrimidine-4,6-diamine OR0612; - 2-(2-((5-(2-aminopyrimidin-5-yl)-2-methylphenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0613; - 2-(2-((4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0614; - 3'-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4'-methyl-[1,1'-biphenyl]-4-sulfonamide OR0615; - N-(5-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)pyridin-2-yl)-4-methylpiperazine-1-carboxamide OR0616; - 2-(2-((4-methyl-4'-(morpholinosulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0617; - 3'-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-N,N,4'-trimethyl-[1,1'-biphenyl]-4-sulfonamide OR0618; - 2-(2-((4'-((dimethylamino)methyl)-4-methyl-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0619; - 2-(2-((2-methyl-5-(pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0620; - (5-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)pyridin-2-yl)(morpholino)methanone OR0621; - methyl 5-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)picolinate OR0622; - N-(5-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)pyridin-2-yl)-4-methylpiperazine-1-sulfonamide OR0625; - 2-(2-((5-(1H-indol-5-yl)-2-methylphenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0626; - 2-(2-((2-methyl-5-(6-((4-methylpiperazin-1-yl)sulfonyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0627; - 2-(2-((2-methyl-5-(6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0629; - 2-((5-(3-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4-methylphenyl)pyridin-2-yl)oxy)-1-(4-methylpiperazin-1-yl)ethan-1-one OR0630; - 2-(2-(methyl(4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0631; - 2-(2-(ethyl(4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-di-amine OR0632; - 2-(2-((5-fluoro-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0633; - 2-(2-((3'-methoxy-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0635; - 2-(2-(iso-propyl(4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0636; - 2-(2-(iso-butyl(4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0637; - 2-(2-((4'-((4-ethylpiperazin-1-yl)sulfonyl)-4-methyl-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0638; - 2-(2-((4-methyl-4'-(piperazin-1-ylsulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0639; - 2-(2-((4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)oxazol-4-yl)pyrimidine-4,6-diamine OR0640; - 2-(2-((2'-chloro-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0641; - 2-(2-((4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-2'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0642; - 2-(2-((2'-fluoro-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0643; - 2-(2-((2'-fluoro-6'-methoxy-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0644; - 2-(2-((2'-methoxy-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0645; - 2-(2-((4-methyl-4'-(piperidin-4-ylsulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0646; - 2-(2-((2',6'-difluoro-4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0647; - 2-(2-((4'-((4-aminopiperidin-1-yl)sulfonyl)-4-methyl-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0648; - 2-(4-((3'-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4'-methyl-[1,1'-biphenyl]-4-yl)sulfonyl)piperazin-1-yl)acetic acid OR0649; - 2-(2-((4-methyl-4'-((4-methylpiperazin-1-yl)sulfonyl)-3'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0650; - N-(2-aminoethyl)-3'-((4-(4,6-diaminopyrimidin-2-yl)thiazol-2-yl)(propyl)amino)-4'-methyl-[1,1'-biphenyl]-4-sulfonamide OR0651; - 2-(2-((2-methyl-5-(4-methyl-6-((4-methylpiperazin-1-yl)sulfonyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0652; - 2-(2-((5-bromo-2-methylphenyl)(isobutyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0637-1; - 2-(2-((5-bromo-2-methylphenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0652-1; - 2-(2-((2-methyl-5-(2-methyl-6-((4-methylpiperazin-1-yl)sulfonyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0653; - 2-(2-((5-(6-methoxy-4-(trifluoromethyl)pyridin-3-yl)-2-methylphenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0654; - 2-(2-((5-(6-hydroxy-4-(trifluoromethyl)pyridin-3-yl)-2-methylphenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0655; - 2-(2-((2-methyl-5-(6-((4-methylpiperazin-1-yl)sulfonyl)-4-(trifluoromethyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0656; 2-(2-((2-methyl-5-(6-((4-methylpiperazin-1-yl)sulfonyl)-2-(trifluoromethyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0657; and - 2-(2-((2-methyl-5-(6-(piperazin-1-ylsulfonyl)-2-(trifluoromethyl)pyridin-3-yl)phenyl)(propyl)amino)thiazol-4-yl)pyrimidine-4,6-diamine OR0658 2. The compound of claim 1 selected from the group consisting of:

16. 10. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

17. 17. The pharmaceutical composition of claim 16, further comprising an inhibitor of the de novo nucleotide biosynthetic pathway, in particular a ribonucleotide reductase inhibitor, preferably thymidine.

18. 17. The pharmaceutical composition of claim 16 for use in the treatment of cancer, preferably liquid cancer, more preferably acute lymphoblastic leukemia, even more preferably T-cell acute lymphoblastic leukemia.

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