Pyridine-2-derivatives as smoothened receptor modulators

摘要

The present application relates to compounds of Formula (I), and Formula (II), or pharmaceutically acceptable salt thereof, wherein A, X, Y, Z, e, f, R1, R2, R3, R4, R5, R5b, R6, R7, R8, R9, R10, R11, R20, R21, R22 and R23 are defined herein. These novel pyridine derivatives that are useful in therapy, in particular for treating diseases or conditions mediated by Smo, including the treatment of abnormal cell growth, such as cancer, in mammals. Additional embodiments relate to methods of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.;

主权项

1. A compound of formula (1),wherein:
A is selected from N and C—R13; X is N and Y is C—R12; R1, R2, R3, R4, R6, R12 and R13 are independently selected from the group consisting of hydrogen, —(CR14R15)nhalo, —(CR14R15)nCN, —(CR14R15)nCF3, —(CR14R15)n(C1-C10alkyl), —(CR14R15)n(C2-C6alkenyl), —(CR14R15)n(CR14R15)n(C2-C6alkynyl), —CR14R15)nNR16 R17, —(CR14R15)nOR16, —(CR14R15)nC(O)R16, —(CR14R15)nC(O)R16, —(CR14R15)nS(O)R16, —(CR14R15)nS(O)2R16, —(CR14R15)nS(O)2NR16R17, —(CR14R15)nNR16S(O)2R17, —(CR14R15)n(C3-C10cycloalkyl), —(CR14R15)n(3-12 membered heterocyclyl), —(CR14R15)n(C6-C10aryl), and —(CR14R15)n(5-12 membered heteroaryl); R5 is selected from the group consisting of halo, C1-C10 alkyl, and —CF3; each R7, R8, R9, and R10 is independently selected from the group consisting of hydrogen, —(CR14R15)nhalo, —(CR14R15)nCN, —(CR14R15)nCF3, —(CR14R15)n(C1-C10alkyl), —(CR14R15)n(C2-C6alkenyl), —(CR14R15)n(C2-C6alkenyl), —(CR14R15)nNR16R17, —(CR14R15)nOR16, —(CR14R15)nC(O)R16, 13 (CR14R15)nC(O))R16, —(CR15R15)nS(O)2R16, —(CR14R15)nS(O)2NR16R17, —(CR13R15)nNR16S(O)2R17, —(CR14R15)n(C3-C10cycloalkyl), —(CR14R15)n(3-12 membered heterocyclyl), —(CR14R15)n(C6-C10aryl), and —(CR14R15)n(5-12 membered heteroaryl); or each R7and R8, or R9 and R10, together with the carbon to which they are attached, may combine to form a carbonyl group; or each R7 and R9, or R8 and R10, may combine to form a 5 or 6 membered ring when said R7 and said R9, or said R8 and said R10, are each —(CR14R15)n(C1-C10alkyl); R11is selected from the group consisting of hydrogen —(CR14R15)nhalo, —(CR14R15)—nCN, —(CR14R15)nCF3, —(CR14R15)n(C1-C10alkyl), —(CR14R15)n(C2-C6alkenyl), —(CR14R15)n(C2-C6alkynyl), —(CR14R15)nNRARB, —(CR14R15)nNRAORB, —(CR14R15)nNRAC(O)RB, —(CR14R15)nNRAC(O)ORB, —(CR14R15)nORA, —(CR14R15)nC(O)RA, —(CR14R15)nC(O)ORA, —(CR14R15)nS(O)RA, —(CR14R15)nS(O)2RA, —(CR14R15)nS(O)2NRARB, —(CR14R15)nNRAS(O)2RB, —(CR14R15)nC(O)NRARB, —(CR14R15)n(C3-C10cycloalkyl), —(CR14R15)n(3-12 membered heterocyclyl), —(CR14R15)n(C6-C10aryl), and —(CR14R15)n(5-12 membered heteroaryl wherein each of said C3-C10cycloalkyl, said 3-12 membered heterocyclyl, said C6-C10aryl, and said 5-12 membered heteroaryl groups is substituted with one or more R14 groups; or R11 and R13, together with the carbon to which they are attached, may combine to form a 3-12 membered heterocyclyl group which is substituted with one or more R14 groups; RA and RB are independently selected from the group consisting of hydrogen, —(CR14R15)nhalo, —(CR14R15)nCN, —(CR14R15)nCF3, —(CR14R15)n(C1-C10alkyl), —(CR14R15)n(C2-C5alkenyl), —(CR14R15)n(C2-C6alkynyl), —(CR14R15)nNR16R17, —(CR14R15)nNR16OR17, —(CR14R15)nNR16C(O)R17, —(CR14R15)nNR16C(O)OR17, —(CR14R15)nOR16, —(CR14R15)nC(O)R16, —(CR14R15)nC(O)OR16, —(CR14R15)nS(O)R16, —(CR14R15)nS(O)2R16, —(CR14R15)nS(O)2NR16R17, —(CR14R15)nNR16S(O)2R17, —(CR14R15)n(C3-C10cycloalkyl), —(CR14R15)n(3-12 membered heterocyclyl), —(CR14R15)n(C6-C10aryl), and —(CR14R15)n-(5-12 membered heteroaryl), wherein each of said C3-C10cycloalkyl, said 3-12 membered heterocyclyl, said C6-C10aryl, and said 5-12 membered heteroaryl groups is substituted with one or more R14 groups; each R14, R15, R16 and R17 is independently selected from the group consisting of hydrogen, —(CR24R25)nhalo, —(CR24R25)nCF3, —(CR24R25)n(C1-C10alkyl), —(CR24R25)n(C2-C6alkenyl), —(CR24R25)nC2-C6alkynyl), —(CR24R25)nOR18, —(CR24R25)n,NR18R19, —(CR24R25)nCN, —(CR24R25)nS(O)2R18, —CR24R25 )nS(O)2NR18R19, —(CR24R25)n(C3-C10cycloalkyl), —CR24R25)n(3-12 membered heterocyclyl), —(CR24R25)n(C6-C10aryl), and —(CR24R25)n(5-12 membered heteroaryl), wherein each of said C3-C10cycloalkyl, said 3-12 membered heterocyclyl, said C6-C10aryl, and said 5-12 membered heteroaryl groups is substituted with one or more R18 groups; each R18, R19, R24 and R25 is independently selected from the group consisting of hydrogen, —(CH2)n(C1-C10alkyl), —(CH2)n(C3-C10cycloalkyl), —(CH2)n(3-12 membered heterocyclyl), —(CH2)n(C6-C10aryl), and —(CH2)n(5-12 membered heteroaryl): e is 2; f is 2; and each n is independently 0, 1, 2, 3, 4, 5, or 6; or a pharmaceutically acceptable salt thereof.