PYRIMIDINES DERIVATIVES AND THEIR USE AS KINASE INHIBITORSAt least one chemical entity chosen from compounds of Formula 1 and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, is described herein. Pharmaceutical compositions comprising at least one chemical entity of Formula 1, together with at least one pharmaceutically acceptable vehicle chosen from carriers adjuvants, and excipients, are described. Methods of treating patients suffering from certain diseases responsive to inhibition of Btk activity and/ or B-cell activity are described. Methods for determining the presence of Btk in a sample are described.A compound chosen from compounds of Formula 1 : (Formula 1) and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein Z1 is CR and Z2 is N or Z1 is N and Z2 is CR;A is chosen from optionally substituted phenylene, optionally substituted pyridylidene, optionally substituted 2-oxo-l,2-dihydropyridinyl, wherein * indicates the point of attachment to the group -L-G and the broken bond indicates the point of attachment to the amino group; X1 is chosen from N and CR7; X2 is chosen from N and CR7; and X3 is chosen from N and CR7; and wherein no more than one of X1, X2, and X3 is N, and R7 is chosen from hydrogen, hydroxy, cyano, halo, optionally substituted lower alkyl, and optionally substituted lower alkoxy; L is chosen from optionally substituted Co-C4alkylene, -O-optionally substituted Co-C4alkylene, -(C0-C4alkylene)(SO)-, -(C0-C4alkylene)(SO2)-; and -(C0-C4alkylene)(C=O)-; G is chosen from hydrogen, halo, hydroxy, alkoxy, nitro, optionally substituted alkyl, optionally substituted amino, optionally substituted carbamimidoyl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R and R1 are independently chosen from hydrogen and optionally substituted lower alkyl; W is chosen from optionally substituted phenylene and optionally substituted pyridylidene; Q is chosen fromC ?»-N N — C I™ N- fC f C — N , and N — ? C — NI I ' I ' I R I iRn R 12 Ri p R 11 R 13 R *113 14 R 15 whereinR10 and R11 are independently chosen from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl; andR12, Ri3, Ri4, and R15 are independently chosen from hydrogen,Ci-C6 alkyl,Ci-C6 haloalkyl, phenyl, substituted phenyl chosen from mono-, di-, and tri- substituted phenyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, Ci-C6 alkyl, Ci-C6 alkoxy, (Ci-C6 alkyloxy)Ci-C6 alkoxy, Ci-C6 perfluoroalkyl, Ci-C6 perfluoroalkoxy, mono-(Ci-C6 alkyl)amino, di(Ci-C6 alkyl) amino, and amino (Ci -C6 alkyl), heteroaryl, and substituted heteroaryl chosen from mono-, di-, and tri- substituted heteroaryl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, Ci-C6 alkyl, Ci-C6 alkoxy, (Ci-C6 alkyloxy)Ci-C6 alkoxy, Ci-C6 perfluoroalkyl, Ci-C6 perfluoroalkoxy, mono-(Ci-C6 alkyl)amino, di(Ci-C6 alkyl) amino, and amino (Ci -C6 alkyl); and R2 is chosen from optionally substituted aryl and optionally substituted heteroaryl, provided that, the compound of Formula 1 is not chosen fromN-(4-(2-(4-(4-acetylpiperazine-l-carbonyl)phenylamino)pyrimidin-4- yl)phenyl)benzamide ; l-(4-(2-(4-(4-acetylpiperazine-l-carbonyl)phenylamino)pyrimidin-4-yl)phenyl)-3- phenylurea; N-(3-(2-(3,4,5-Trimethoxyphenylamino)pyrimidin-4-yl)phenyl)pyridine-3- carboxamide; N-(3-(2-(3,4,5-Trimethoxyphenylamino)pyrimidin-4-yl)phenyl)-5-methylisoxazole-3- carboxamide;N-(3-(2-(3-sulfamoylphenylamino)pyrimidin-4-yl)phenyl)furan-2-carboxamide; N-(3-(2-(3-methoxyphenylamino)pyrimidin-4-yl)phenyl)-N-methylfuran-2- carboxamide;N-(3-(2-(3-methoxyphenylamino)pyrimidin-4-yl)phenyl)furan-2-carboxamide; N-(3-(2-(3-hydroxyphenylamino)pyrimidin-4-yl)phenyl)furan-2-carboxamide; N-(3-(2-(3-aminophenylamino)pyrimidin-4-yl)phenyl)picolinamide; N-(3-(2-(3-aminophenylamino)pyrimidin-4-yl)phenyl)thiophene-2-carboxamide; N-(3-(2-(3-aminophenylamino)pyrimidin-4-yl)phenyl)furan-2-carboxamide; N-(5-(2-(3-aminophenylamino)pyrimidin-4-yl)-2-methoxyphenyl)thiophene-2- carboxamide;N-(4-(2-(3-aminophenylamino)pyrimidin-4-yl)phenyl)thiophene-2-carboxamide; N-(4-(2-(3-aminophenylamino)pyrimidin-4-yl)phenyl)furan-2-carboxamide; N-(4-(2-(3-hydroxyphenylamino)pyrimidin-4-yl)phenyl)thiophene-2-carboxamide; N-(3-(2-(3-sulfamoylphenylamino)pyridin-4-yl)phenyl)furan-2-carboxamide; N-(3-(2-(3-methoxyphenylamino)pyridin-4-yl)phenyl)-N-methylfuran-2- carboxamide;N-(3-(2-(3-methoxyphenylamino)pyridin-4-yl)phenyl)furan-2-carboxamide; N-(3-(2-(3-hydroxyphenylamino)pyridin-4-yl)phenyl)furan-2-carboxamide; N-(3-(2-(3-aminophenylamino)pyridin-4-yl)phenyl)picolinamide; N-(3-(2-(3-aminophenylamino)pyridin-4-yl)phenyl)thiophene-2-carboxamide; N-phenyl-4-(2-(phenylamino)pyrimidin-4-yl)benzamide; 4-(5-methyl-2-(phenylamino)pyrimidin-4-yl)-N-phenylbenzamide; N-(4-(2-(3-hydroxyphenylamino)pyrimidin-4-yl)phenyl)-2-phenoxyacetamide; and 2-phenoxy-N- (4- (2- (3 - sulf amoylphenylamino)pyrimidin-4-yl)phenyl) acetamide .
피리미딘 유도체 및 키나제 억제제로서의 그의 용도본원에는, 하기 화학식 1의 화합물, 및 그의 제약상 허용가능한 염, 용매화물, 킬레이트화물, 비-공유 착물, 전구약물, 및 혼합물로부터 선택된 1종 이상의 화학 물질이 기재된다. 화학식 1의 1종 이상의 화학 물질을 담체, 보조제 및 부형제로부터 선택된 1종 이상의 제약상 허용가능한 비히클과 함께 포함하는 제약 조성물이 기재된다. Btk 활성 및/또는 B-세포 활성 억제에 대해 반응성인 특정 질환을 앓고 있는 환자를 치료하는 방법이 기재된다. 샘플 중 Btk의 존재를 결정하는 방법이 기재된다. <화학식 1> 하기 화학식 1의 화합물, 및 그의 제약상 허용가능한 염, 용매화물, 킬레이트화물, 비-공유 착물, 전구약물, 및 혼합물로부터 선택된 화합물. <화학식 1>  상기 식에서, Z1은 CR이고 Z2는 N이거나, 또는 Z1은 N이고 Z2는 CR이고; A는 임의로 치환된 페닐렌, 임의로 치환된 피리딜리덴, 임의로 치환된 2-옥소-1,2-디히드로피리디닐,   로부터 선택되며, 여기서 *는 -L-G 기에 대한 결합점을 나타내고, 끊어져 있는 결합은 아미노기에 대한 결합점을 나타내며; X1은 N 및 CR7로부터 선택되고; X2는 N 및 CR7로부터 선택되며; X3은 N 및 CR7로부터 선택되고; 여기서 X1, X2 및 X3 중 1개 이하는 N이며, R7은 수소, 히드록시, 시아노, 할로, 임의로 치환된 저급 알킬, 및 임의로 치환된 저급 알콕시로부터 선택되며; L은 임의로 치환된 C0-C4알킬렌, -O-임의로 치환된 C0-C4알킬렌, -(C0-C4알킬렌)(SO)-, -(C0-C4알킬렌)(SO2)-; 및 -(C0-C4알킬렌)(C=O)-로부터 선택되고; G는 수소, 할로, 히드록시, 알콕시, 니트로, 임의로 치환된 알킬, 임의로 치환된 아미노, 임의로 치환된 카르밤이미도일, 임의로 치환된 헤테로시클로알킬, 임의로 치환된 시클로알킬, 임의로 치환된 아릴, 및 임의로 치환된 헤테로아릴로부터 선택되며; R 및 R1은 수소 및 임의로 치환된 저급 알킬로부터 독립적으로 선택되고; W는 임의로 치환된 페닐렌 및 임의로 치환된 피리딜리덴으로부터 선택되며; Q는  로부터 선택되고; 여기서 R10 및 R11은 수소, C1-C6 알킬, 및 C1-C6 할로알킬로부터 독립적으로 선택되며; R12, R13, R14, 및 R15는 수소, C1-C6 알킬, C1-C6 할로알킬, 페닐, 치환기가 히드록시, 니트로, 시아노, 아미노, 할로, C1-C6 알킬, C1-C6 알콕시, (C1-C6 알킬옥시)C1-C6 알콕시, C1-C6 퍼플루오로알킬, C1-C6 퍼플루오로알콕시, 모노-(C1-C6 알킬)아미노, 디(C1-C6 알킬)아미노, 및 아미노(C1-C6 알킬)로부터 독립적으로 선택되는, 일-, 이- 및 삼-치환된 페닐로부터 선택된 치환된 페닐, 헤테로아릴, 및 치환기가 히드록시, 니트로, 시아노, 아미노, 할로, C1-C6 알킬, C1-C6 알콕시, (C1-C6 알킬옥시)C1-C6 알콕시, C1-C6 퍼플루오로알킬, C1-C6 퍼플루오로알콕시, 모노-(C1-C6 알킬)아미노, 디(C1-C6 알킬)아미노, 및 아미노(C1-C6 알킬)로부터 독립적으로 선택되는, 일-, 이- 및 삼-치환된 헤테로아릴로부터 선택된 치환된 헤테로아릴 로부터 독립적으로 선택되고; R2는 임의로 치환된 아릴 및 임의로 치환된 헤테로아릴로부터 선택되되, 단, 화학식 1의 화합물은, N-(4-(2-(4-(4-아세틸피페라진-1-카르보닐)페닐아미노)피리미딘-4-일)페닐)벤즈아미드; 1-(4-(2-(4-(4-아세틸피페라진-1-카르보닐)페닐아미노)피리미딘-4-일)페닐)-3-페닐우레아; N-(3-(2-(3,4,5-트리메톡시페닐아미노)피리미딘-4-일)페닐)피리딘-3-카르복스아미드; N-(3-(2-(3,4,5-트리메톡시페닐아미노)피리미딘-4-일)페닐)-5-메틸이속사졸-3-카르복스아미드; N-(3-(2-(3-술파모일페닐아미노)피리미딘-4-일)페닐)푸란-2-카르복스아미드; N-(3-(2-(3-메톡시페닐아미노)피리미딘-4-일)페닐)-N-메틸푸란-2-카르복스아미드; N-(3-(2-(3-메톡시페닐아미노)피리미딘-4-일)페닐)푸란-2-카르복스아미드; N-(3-(2-(3-히드록시페닐아미노)피리미딘-4-일)페닐)푸란-2-카르복스아미드; N-(3-(2-(3-아미노페닐아미노)피리미딘-4-일)페닐)피콜린아미드; N-(3-(2-(3-아미노페닐아미노)피리미딘-4-일)페닐)티오펜-2-카르복스아미드; N-(3-(2-(3-아미노페닐아미노)피리미딘-4-일)페닐)푸란-2-카르복스아미드; N-(5-(2-(3-아미노페닐아미노)피리미딘-4-일)-2-메톡시페닐)티오펜-2-카르복스아미드; N-(4-(2-(3-아미노페닐아미노)피리미딘-4-일)페닐)티오펜-2-카르복스아미드; N-(4-(2-(3-아미노페닐아미노)피리미딘-4-일)페닐)푸란-2-카르복스아미드; N-(4-(2-(3-히드록시페닐아미노)피리미딘-4-일)페닐)티오펜-2-카르복스아미드; N-(3-(2-(3-술파모일페닐아미노)피리딘-4-일)페닐)푸란-2-카르복스아미드; N-(3-(2-(3-메톡시페닐아미노)피리딘-4-일)페닐)-N-메틸푸란-2-카르복스아미드; N-(3-(2-(3-메톡시페닐아미노)피리딘-4-일)페닐)푸란-2-카르복스아미드; N-(3-(2-(3-히드록시페닐아미노)피리딘-4-일)페닐)푸란-2-카르복스아미드; N-(3-(2-(3-아미노페닐아미노)피리딘-4-일)페닐)피콜린아미드; N-(3-(2-(3-아미노페닐아미노)피리딘-4-일)페닐)티오펜-2-카르복스아미드; N-페닐-4-(2-(페닐아미노)피리미딘-4-일)벤즈아미드; 4-(5-메틸-2-(페닐아미노)피리미딘-4-일)-N-페닐벤즈아미드; N-(4-(2-(3-히드록시페닐아미노)피리미딘-4-일)페닐)-2-페녹시아세트아미드; 및 2-페녹시-N-(4-(2-(3-술파모일페닐아미노)피리미딘-4-일)페닐)아세트아미드로부터 선택되지 않는다.