US 2013/0210800 A1Published application

Pyridine-2-derivatives as smoothened receptor modulators

AssigneePfizer Inc.

InventorsSajiv Krishnan Nair, Simon Paul Planken

Life of this patent

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Abstract

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.

Claims33

Dependent claims

A compound of formula (I),

wherein:
A is selected from N and C—R13;
X and Y are independently selected from N and C—R12, provided that at least one of X and Y is N;
R1, R2, R3, R4, R6, R12 and R13 are independently selected from hydrogen, —(CR14R15)nhalo, —(CR14R15)nCN, —(CR14R15)nCF3, —(CR14R15)n(C1-C10alkyl), —(CR14R15)n(C2-C6alkenyl), —(CR14R15)n(C2-C6alkynyl), —(CR14R15)nNR16R17, —(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);
R5 is selected from halo, C1-C10 alkyl, and —CF3,
each R7, R8, R9, and R10 is independently selected from hydrogen, —(CR14R15)nhalo, —(CR14R15)nCN, —(CR14R15)nCF3, —(CR14R15)n(C1-C10alkyl), —(CR14R15)n(C2-C6alkenyl), —(CR14R15)n(C2-C6alkynyl), —(CR14R15)nNR16R17, —(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);
or each R7 and 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);
R11 is selected from 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 hydrogen, —(CR14R15)nhalo, —(CR14R15)—nCN, —(CR14R15)nCF3, —(CR14R15)n(C1-C10alkyl), —(CR14R15)n(C2-C6alkenyl), —(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), —(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 hydrogen, —(CR24R25)nhalo, —(CR24R25)nCF3, —(CR24R25)n(C1-C10alkyl), —(CR24R25)n(C2-C6alkenyl), —(CR24R25)n(C2-C6alkynyl), —(CR24R25)nOR18, —(CR24R25)nNR18R19, —(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 C-6-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 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 1 or 2;
f is 1 or 2;
and
each n is independently selected from 0, 1, 2, 3, 4, 5, and 6;
or
a pharmaceutically acceptable salt thereof.

16 more elements

A compound of formula (II),

wherein:
X and Y are independently selected from N and C—R12, provided that at least one of X and Y is N;
Z is selected from NR11b and CR13NR14R11b;
R1, R2, R3, R4, R5b, R6, R12 and R13 are independently selected from hydrogen, —(CR14R15)nhalo, —(CR14R15)nCN, —(CR14R15)nCF3, —(CR14R15)n(C1-C10alkyl), —(CR14R15)n(C2-C6alkenyl), —(CR14R15)n(C2-C6alkynyl), —(CR14R15)nNR16R17, —(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);
each R20, R21, R22 and R23 is independently selected from hydrogen, —(CR14R15)nhalo, —(CR14R15)nCN, —(CR14R15)nCF3, —(CR14R15)n(C1-C10alkyl), —(CR14R15)n(C2-C6alkenyl), —(CR14R15)n(C2-C6alkynyl), —(CR14R15)nNR16R17, —(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);
or each R20 and R21, or R22 and R23, together with the carbon to which they are attached, may combine to form a carbonyl group;
or each R20 and R22, or R21 and R23, may combine to form a 5 or 6 membered ring when said R20 and said R22, or said R21 and said R23, are each —(CR14R15)n(C1-C10alkyl).
R11b is selected from C(O)RA and S(O)2RA;
RA is selected from —(CR14R15)nCF3, —(CR14R15)n(C1-C10alkyl), —(CR14R15)n(C2-C6alkenyl), —(CR14R15)n(C2-C6alkynyl), —(CR14R15)nNR16R17, —(CR14R15)nNR16OR17, —(CR14R15)nNR16C(O)R17, —(CR14R15)nNR16C(O)OR17, —(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), —(CR14R15)mhalo, —(CR14R15)mCN, —(CR14R15)mOR16, —(CR14R15)mC(O)R16, —(CR14R15)mC(O)OR16, —(CR14R15)mS(O)R16, —(CR14R15)mS(O)2R16, and —(CR14R15)mS(O)2NR16R17, wherein said C3-C10cycloalkyl, said 3-12 membered heterocyclyl, said C6-C10aryl, and said 5-12 membered heteroaryl are each substituted with one or more R14 groups;
each R14, R15, R16 and R17 is independently selected from hydrogen, —(CR24R25)nhalo, —(CR24R25)nCF3, —(CR24R25)nC1-C10alkyl, —(CR24R25)nC2-C6alkenyl, —(CR24R25)nC2-C6alkynyl, —(CR24R25)nOR18, —(CR24R25)nNR18R19, —(CR24R25)nCN, (CR24R25)nS(O)2R18, —(CR24R25)nS(O)2NR18R19, —(CR24R25)nC3-C10cycloalkyl, —(CR24R25)n3-12 membered heterocyclyl, —(CR24R25)nC6-C10aryl, and —(CR24R25)n5-12 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 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;
each n is independently selected from 0, 1, 2, 3, 4, 5, and 6;
and
each m is independently selected from 1, 2, 3, 4, 5, and 6;
or
a pharmaceutically acceptable salt thereof.

15 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound of formula (I),

wherein:
A is selected from N and C—R13;
X and Y are independently selected from N and C—R12, provided that at least one of X and Y is N;
R1, R2, R3, R4, R6, R12 and R13 are independently selected from hydrogen, —(CR14R15)nhalo, —(CR14R15)nCN, —(CR14R15)nCF3, —(CR14R15)n(C1-C10alkyl), —(CR14R15)n(C2-C6alkenyl), —(CR14R15)n(C2-C6alkynyl), —(CR14R15)nNR16R17, —(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);
R5 is selected from halo, C1-C10 alkyl, and —CF3,
each R7, R8, R9, and R10 is independently selected from hydrogen, —(CR14R15)nhalo, —(CR14R15)nCN, —(CR14R15)nCF3, —(CR14R15)n(C1-C10alkyl), —(CR14R15)n(C2-C6alkenyl), —(CR14R15)n(C2-C6alkynyl), —(CR14R15)nNR16R17, —(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);
or each R7 and 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);
R11 is selected from 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 hydrogen, —(CR14R15)nhalo, —(CR14R15)—nCN, —(CR14R15)nCF3, —(CR14R15)n(C1-C10alkyl), —(CR14R15)n(C2-C6alkenyl), —(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), —(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 hydrogen, —(CR24R25)nhalo, —(CR24R25)nCF3, —(CR24R25)n(C1-C10alkyl), —(CR24R25)n(C2-C6alkenyl), —(CR24R25)n(C2-C6alkynyl), —(CR24R25)nOR18, —(CR24R25)nNR18R19, —(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 C-6-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 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 1 or 2;
f is 1 or 2;
and
each n is independently selected from 0, 1, 2, 3, 4, 5, and 6;
or
a pharmaceutically acceptable salt thereof.

16 more elements