US 10,294,237 B2 · Bicyclic heterocyclic amide derivative

Abstract

The present invention provides a bicyclic heterocyclic amide derivative of formula (1) wherein ring Q1 is optionally-substituted C6-10 aryl group, etc.; R1 and R2 are independently hydrogen atom, etc.; W1 is optionally-substituted C1-4 alkylene group; W2 is —NR3aC(O)—, etc. wherein R3a is hydrogen atom or C1-6 alkyl group; Cy1 is the following group of formula (11), etc.; ring Q2 is optionally-substituted benzene ring, etc.; n and m are independently 0, 1 or 2, provided that n and m are not simultaneously 0; X is NR5, etc.; R5 is hydrogen atom, etc.; p is 1, 2, 3, 4 or 5; R4 is, independently when two or more exist, hydrogen atom, etc.; and a pharmacologically acceptable salt thereof, which have a potent inhibitory effect on the sphere-forming ability of cancer cells and are useful as an orally-available anti-tumor agent.

A compound of formula (1):

or a pharmaceutically acceptable salt thereof, wherein ring Q1 is optionally-substituted C6-10 aryl group, optionally-substituted C3-10 cycloalkyl group, or optionally-substituted 5- to 10-membered heteroaryl group, wherein the substituents of the C6-10 aryl group, the C3-10 cycloalkyl group, or 5- to 10-membered heteroaryl group are selected from the group consisting of:
(a) halogen;
(b) C1-6 alkyl which is optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, hydroxy, and C1-6 alkoxy;
(c) C1-6 alkoxy which is optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, hydroxy, and C1-6 alkoxy;
(d) cyano;
(e) C6-10 aryl which is optionally substituted with 1 to 4 groups independently selected from the group consisting of halogen, C1-6 alkyl, and C1-6 alkoxy;
(f) 5- or 6-membered heteroaryl which is optionally substituted with 1 to 4 groups independently selected from the group consisting of halogen, C1-6 alkyl, and C1-6 alkoxy;
(g) C6-10 aryloxy which is optionally substituted with 1 to 4 groups independently selected from the group consisting of halogen, C1-6 alkyl, and C1-6 alkoxy;
(h) hydroxy,
(i) amino which is optionally substituted with 1 to 2 independently selected C1-6 alkyl groups;
(j) aminocarbonyl, wherein the amino moiety is optionally substituted with 1 to 2 independently selected C1-6 alkyl groups;
(k) C1-6 alkoxy-carbonyl, wherein the alkoxy moiety is optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, hydroxy, and C1-6 alkoxy;
(l) C1-6 alkyl-carbonyl, wherein the alkyl moiety is optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, hydroxy, and C1-6 alkoxy;
(m) C1-6 alkylsulfonyl, wherein the alkyl moiety is optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, hydroxy, and C1-6 alkoxy;
(n) C1-6 alkyl-carbonylamino, wherein the alkyl moiety is optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, hydroxy, and C1-6 alkoxy;
(o) C1-6 alkylsulfonylamino, wherein the alkyl moiety is optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, hydroxy, and C1-6 alkoxy;
(p) C1-6 alkoxy-carbonylamino, wherein the alkoxy moiety is optionally substituted 1 to 3 groups independently selected from the group consisting of halogen, hydroxy, and C1-6 alkoxy;
(q) C1-6 alkyl-carbonyloxy, wherein the alkyl moiety is optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, hydroxy, and C1-6 alkoxy;
(r) aminosulfonyl, wherein the amino moiety is optionally substituted with 1 to 2 independently selected C1-6 alkyl groups;
and
(s) C3-10 cycloalkyl, which is optionally substituted with 1 to 4 groups independently selected from the group consisting of halogen, hydroxy, and C1-6 alkoxy;
R1 and R2 are independently hydrogen, halogen, or C1-6 alkyl which is optionally substituted with 1 to 3 independently selected halogen groups;
W1 is optionally-substituted C1-4 alkylene group, wherein the substituents of C1-4 alkylene group are selected from the group consisting of halogen, hydroxy, and C1-6 alkoxy;
W2-Cy1 is —NR3aC(O)-Cy1, —NR3aC(O)O-Cy1, —NR3aC(O)OCH2-Cy1, —NR3aC(O)NR3b-Cy1, —NR3aC(O)NR3bCH2-Cy1, —NR3aC(O)CH2O-Cy1, —NR3aC(O)CH2-Cy1, —NR3aC(O)CH2CH2-Cy1, —C(O)NR3a-Cy1, —C(O)NR3aCH2-Cy1, —C(O)NR3aCH2CH2-Cy1, or —NR3aC(O)—CR3c═CR3d-Cy1 wherein R3a and R3b are independently hydrogen or C1-6 alkyl;
and R3c and R3d are independently hydrogen, fluorine, or C1-6 alkyl;
and
Cy1 is a group of the following formula (11), (12), (13), or (15):
wherein ring Q2 is an optionally-substituted benzene ring, an optionally-substituted pyridine ring, an optionally-substituted pyrimidine ring, an optionally-substituted pyridazine ring, or an optionally-substituted pyrazine ring, wherein the substituents of the benzene ring, pyridine ring, pyrimidine ring, pyridazine ring, or pyrazine ring are selected from the group consisting of:
(a) halogen,
(b) C1-6 alkyl which is optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, hydroxy, and C1-6 alkoxy;
(c) C1-6 alkoxy which is optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, hydroxy, and C1-6 alkoxy;
(d) cyano,
(e) C6-10 aryl which is optionally substituted with 1 to 4 groups independently selected from the group consisting of halogen, C1-6 alkyl, and C1-6 alkoxy;
(f) 5- or 6-membered heteroaryl which is optionally substituted with 1 to 4 groups independently selected from the group consisting of halogen, C1-6 alkyl, and C1-6 alkoxy;
(g) C6-10 aryloxy which is optionally substituted with 1 to 4 groups independently selected from the group consisting of halogen, C1-6 alkyl, and C1-6 alkoxy;
(h) hydroxy;
(i) amino which is optionally substituted with 1 to 2 independently selected C1-6 alkyl groups;
(i) aminocarbonyl, wherein the amino moiety is optionally substituted with 1 to 2 independently selected C1-6 alkyl groups;
(k) C1-6 alkoxy-carbonyl, wherein the alkoxy moiety is optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, hydroxy, and C1-6 alkoxy;
(l) C1-6 alkyl-carbonyl, wherein the alkyl moiety is optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, hydroxy, and C1-6 alkoxy;
(m) C1-6 alkylsulfonyl, wherein the alkyl moiety is optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, hydroxy, and C1-6 alkoxy;
(n) C1-6 alkyl-carbonylamino, wherein the alkyl moiety is optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, hydroxy, and C1-6 alkoxy;
(o) C1-6 alkylsulfonylamino, wherein the alkyl moiety is optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, hydroxy, and C1-6 alkoxy;
(p) C1-6 alkoxy-carbonylamino, wherein the alkoxy moiety is optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, hydroxy, and C1-6 alkoxy;
(q) C1-6 alkyl-carbonyloxy, wherein the alkyl moiety is optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, hydroxy, and C1-6 alkoxy;
(r) aminosulfonyl, wherein the amino moiety is optionally substituted with 1 to 2 independently selected C1-6 alkyl groups;
and
(s) C3-10 cycloalkyl which is optionally substituted with 1 to 4 groups independently selected from the group consisting of halogen, hydroxy, and C1-6 alkoxy;
ring Q3 is an optionally-substituted 5-membered heteroaryl ring;
n and m are independently 0, 1 or 2, provided that n and m are not simultaneously 0;
X and Z are independently NR5, —NR3eC(O)—, —C(O)NR3e—, or O wherein R5 is hydrogen or C1-6 alkyl which is optionally substituted with 1 to 3 independently selected halogen groups;
and R3e is hydrogen or C1-6 alkyl;
p is 1, 2, 3, 4 or 5;
and
R4 is, independently when two or more exist, hydrogen, halogen, hydroxy, oxo, a C1-6 alkyl group which optionally substituted with 1 to 3 independently selected halogen groups, or a C1-6 alkoxy group which is optionally substituted with 1 to 3 independently selected halogen groups;
or
when two R4 are attached to the same carbon atom or adjacent carbon atoms on the ring, they may be combined with the carbon atom(s) to form
(1) a 5- to 8-membered saturated or partially-unsaturated carbocyclic ring which is optionally substituted with 1 to 4 groups independently selected from the group consisting of halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, or
(2) a 5- to 8-membered saturated or partially-unsaturated heterocyclic ring which is optionally substituted with 1 to 4 groups independently selected from the group consisting of halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy.

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Bicyclic heterocyclic amide derivative

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Bicyclic heterocyclic amide derivative

Life of this patent

Abstract

Claims36