2 - arilaminoquinazolinas for Treatment of proliferative Diseases

摘要

These compounds are PDK1 inhibitors. Pharmacological compositions are also provided, including compounds and methods for the treatment of proliferative diseases, such as c.nceres, which contains compounds or ingredients. 1. Claim 1: a formula compound (1) or a pharmaceutically acceptable formula salt, R1a is selected from H and halogen; R3a is selected from the isopropylene glycol of C1-6 and c1-6-alcoxyl C1-4; There, both CYCLOPROPYLENE glycol c2-6 and straight CYCLOPROPYLENE glycol c1-6-alcoxilo C1-4 are optional substitutes, replaced by RW group; R4A is selected from h, a thiazole ring and a pyrazole ring,a triazole ring, a tetrazole ring, a pyridine ring, C3-6 cycloalkyl, cyano, halogen, C2-6 alkynyl, C1-6 heteroaryl-C1-4 alkyl, C1-6 heteroaryl-C1-4 alkynyl, - C (= O) Ra, and -C (= O) NRbRc; where the thiazole ring, the pyrazole ring. the triazole ring, the tetrazole ring, the pyridine ring, C1-6 heteroaryl-C1-4 alkyl and C1-6 heteroaryl-C1-4 alkynyl are each optionally substituted by 1 or 2 independently selected Rx '' groups ; Ar1a is selected from phenyl optionally substituted in the target position by a Ry 'or, alternatively, in the position for by a Ry group' ';each Rw is independently selected from halogen, C1-6 alkyl, amino, C1-6-amino alkyl, di-C1-4-alkyl, C1-6 alkoxycarbonyl, and C1-6-carbamyl alkyl; wherein this C1-6 alkyl, and C1-6-amino alkyl are each optionally substituted by a group selected from hydroxyl, C1-6 alkoxy, amino, C1-6-amino alkyl, and di-C1- alkyl 4-amino; each Rx '' is independently selected from halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxycarbonyl, and carbamyl; wherein this C 1-6 alkyl, and C 1-6 alkoxycarbonyl are each optionally substituted by a group selected from hydroxyl, amino, C 1-4 alkyl,and amino-sulfonyl; Ry 'is selected from halogen. C1-6 alkoxy, C1-6 alkyl, carbamyl, amino-sulfonyl, and C1-6-sulfonyl-amino alkyl, wherein this C1-6 alkyl, and C1-6 alkoxy are each substituted by 1 or 2 groups independently selected from hydroxyl, amino, C1-4-alkyl, and amino-sulfonyl; Ry '' is selected from halo-C1-6 alkyl; Ra is selected from H, C1-6 alkoxy, and C2-6 heterocycloalkyl; Rb is selected from H and C1-6 alkyl; and Rc is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroaryl, C 2-6 heterocycloalkyl, C 2-6 heterocycloalkyl-C 1-4 alkyl, and C 1-6 heteroaryl-C 1-4 alkyl;In this case, C1-6 tar is selectively replaced by a group selected from hydroxyl and alcoxyl C1-4, on the understanding that (a) if R3a is piperidin-4-il-oxyl or n-methylpiperidin-4-il-oxyl, R4 will not be selected from tiazol-2-ilo, tiazol-4-ilo, tiazol-5-ilo, 5-methyl-tiazol-2-ilo, - fluorosulfonylmethyl ether-3-selects 3-phenylmethylmethylmethyl from 3, and then comes from 3-fluorotrimethyl-3-methyl (3-yl-yl-jisiro 6-chloro-pyridine-3-yi-methoxy, pyridine-2-yi-methoxy,pyridin-4-yl-methoxy, 1- (pyridin-4-yl) -ethoxy, 6-methoxy-pyridin-2-yl-methoxy, thiazol-5-yl-methoxy, pyrazin-2-yl-methoxy, 5- methyl-iso-oxazol-3-yl, azetidin-3-yloxy, N-methyl-azetidin-3-yloxy, N-isopropyl-azetidin-3-yloxy. pyrrolidin-3-yloxy, N-methyl, and pyrrolidin-3-yl-oxyl; (c) when R4a is ethynyl, then Ar1a is not selected from 3- (2-hydroxy-propan-2-yl) -phenyl, 3- (1-hydroxyethyl) -phenyl, 3-amino-sulfonyl-phenyl, phenyl, 3- (methyl-sulfonyl-amino) -phenyl, 3- (N, N-dimethyl-amino-methyl) -phenyl, 3-amino-sulfonyl-phenyl, and 3-carbamyl-phenyl; (d) when R4a is thiazol-2-yl, then Ar1a is not selected from 3- (methyl-amino-sulfonyl) -phenyl, 3-chloro-phenyl,- iso-4-hydil-iso-4-hydil-4-hydil-iso-iso-4-methyl, 4-hydil-4 ILO, azetidin-3-iloxilo, Phenyl phenyl phenyl 3 phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl;(g) If R4A is cyanogen, R3a is not selected from pyridine-4-il-methoxy, pyridine-2-il-methoxy, and 6-methyl-piridin-2-il-methyl; (H) if R4A is cycloacrylonitrile, R3a is not selected from azetidin-3-il-oxyl; if R4A is hydrogen, R4A is ar1a-3 - (Amin sulfur) - phenyl. ILO Convention No. 10: a formula compound (2) or a pharmaceutically acceptable formula salt, wherein R1 is selected from H and halogen; R2 is selected from h, halogen and alcocilo C1-6; R3 is selected from h, och2-fenilo, o-ch2-het, och2-ch2-het, y-o-hy;wherein Het is 6-membered heteroaryl which is optionally substituted by 1 or 2 groups independently selected from hydroxyl, C 1-6 alkyl, C 1-4 alkoxy, amino, C 1-4 alkyl, di C 1-4 alkyl- amino, and C 1-6 alkylcarbamyl; Hy is a 6-membered heterocycloalkyl, which is optionally substituted by 1 or 2 groups independently selected from hydroxyl, C1-6 alkyl, C1-4 alkoxy, amino, C1-4-amino alkyl, di-C1-4 alkyl- amino, and C 1-6 alkylcarbamyl; and phenyl is optionally substituted by 1 or 2 groups independently selected from hydroxyl, C 1-6 alkyl, C 1-4 alkoxy, amino, C 1-4 alkyl,di-C 1-4 alkyl-amino, and C 1-6 alkyl-carbamyl; R4 is selected from cyano, halogen, C1-6 alkyl, C2-6 alkynyl, C3-6 cycloalkyl, a thiazole ring, a pyrazole ring, and a pyridine ring; each of which is optionally substituted by 1 or 2 groups independently selected from hydroxyl, C 1-6 alkyl, C 1-4 alkoxy, amino, C 1-4 alkyl, and C 1-4 alkyl; wherein this C1-6 alkyl is also optionally substituted by 1 or 2 hydroxyl groups; Ar1 is a fraction of the group of formulas (3),(4)this is it.A is a pyrazole ring, which can be optionally replaced by one or two independent groups, selected from hydroxyl, C1-6 tar, C1-4 toxicology, amino, c1-4-amine tar and di tar c1-4-amine; a 'is selected from - l2-ar2 and - l1-c1; a' is selected from - l2a-ar2a and - CyA; If you are already registered, please log in first.-C (=O)-CH2C (3DO) -Y-CH2-;There, the left end of the can is connected with the phenyl ring, and the right end of the can is connected with cy1; cy1 is selected from the morphine ring, the tetrahydro-2h-pirano ring, the pyridine ring, the dioxypyridine ring and a pichian ring, Each of them is replaced by one or two independently selected groups from halogenation, hydroxyl group, C1-6 tar, alcoxyl C1-4, amino group, c1-4-amine tar, di hydrocarbyl c1-4-amino, c1-6-carbonilo and alcoxyl c1-6-carbonilo; cy1a is selected from mofflin ring, A 2-oxo-pirrolidina ring and a piperdina ring;Each of these substances is replaced by one or two independent groups selected from halogenation, hydroxyl group, C1-6 tar, C1-4 ALCOXY, amino group, c1-4-amino tar, di hydrocarbon c1-4-amino, c1-6-carboilo and alcoxyl c1-6-carbonilo; L2 and L2a are selected from one link, respectively, orY-OCH2-;Ar2 is selected from a pyrazole ring, an oxazol ring, a pyridan ring, a triazole ring, a endosulfan ring, a pyridine ring and a pyridine ring, each of which is replaced by one, two or three independently selected groups from the hydroxyl group and C1-6 hydrocarbon group, C1-4, amino, c1-4-amino hydrocarbyl, and di hydrocarbyl c1-4-amino; ar2a is selected from pyrazoles, triazoles, pyridines, and pyridanes; each ring is selectively replaced by one or two independent groups, selected from hydroxyl, C1-6 hydrocarbyl, alcoxyl C1-4. AminoC1-4-amino and di-hydrocarbyl c1-4-amino; however, it is understood that: (I) when R1 and R2 are both h, R4 is tiazol-2-ilo, R3 is piperididin-4-iloxi substitute, and AR1 is a part of formula group (3),then A 'is not selected from 1,2,4-triazol-1-H-methyl, 1-methyl-pyrazol-3-yl, 2-oxo-pyrrolidinyl, oxazol-5-yl, pyrazol-1-yl , 1-methyl-1,2,4-triazol-2-yl, morpholin-4-yl-carbonyl-methyl, imidazol-2-yl, 2-methyl-thiazol-4-yl, 1,3,5-trimethyl -pyrazol-4-yl, pyrimidin-5-yl, 1,2,4-triazol-1-yl, 4,5-dimethyl-oxazol-2-yl, pyrimidin-5-yl, 2-methoxy-pyrimidin-5 -yl, 6-methoxy-pyridin-3-yl and pyridin-3-yl; (ii) when R1 and R2 are each H, Ar1 is a fraction of the group of formula (3),A 'is selected from 1-methylpyrazole-3-ilo, R3 is selected from pyridine-3-il-methoxy and pyridine-2-il-methoxy, so R4 does not have thiazole-2-ilo; (3) when R1 and R2 are h, R4 are thiazole-2-ilo, R3 are piperidin-4-iloxilo substitutes, AR1 is part of a decision group (4),Therefore, a '' is not selected from morfolin-4-ilo, morfolin-4-il-carbon-metro, pirimidin-5-ilo and pirazol-1-il-metro; (IV) when R1 and R2 are h, R4 are bromine and R3 are piridin-3-il-met, respectively