US 9,957,251 B2Granted

Heterocyclic compound

AssigneeTakeda Pharmaceutical Company Limited

InventorsTakaharu Hirayama, Jun Fujimoto, Douglas Robert Cary, Masanori Okaniwa, Yasuhiro Hirata

Life of this patent

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Abstract

The present invention provides a heterocyclic compound having a CDK8 and/or CDK19 inhibitory effect. The present invention provides a compound represented by formula (I) (in the formula, the symbols are as defined in the description) or a salt thereof.

Claims10

Dependent claims

A compound capable of inhibiting CDK8 and/or CDK19 represented by the formula:

or a salt thereof, wherein
R1 is a hydrogen atom;
R2 is a hydrogen atom, a halogen atom, an amino group or a hydroxy group;
R3 is a hydrogen atom or a halogen atom;
R4 is a 5- or 6-membered monocyclic aromatic heterocyclic group or an 8- to 14-membered fused polycyclic aromatic heterocyclic group, optionally substituted by 1 to 3 substituents selected from the following substituents (1) to (11):
(1) a C1-6 alkyl group optionally having 1 to 7 halogen atoms,
(2) a C1-6 alkyl group substituted by 1 to 7 substituents selected from
(i) a hydroxy group,
(ii) an amino group,
(iii) a C1-6 alkoxy group,
(iv) an optionally halogenated C3-10 cycloalkyl group,
(v) a 5- to 14-membered aromatic heterocyclic group,
(vi) a 3- to 14-membered non-aromatic heterocyclic group,
(vii) a C1-6 alkoxy-carbonyl group, and
(viii) a carbamoyl group,
(3) a C3-10 cycloalkyl group,
(4) a C7-16 aralkyl group optionally substituted by 1 to 7 substituents selected from the following (i) to (iii):
(i) a halogen atom,
(ii) an optionally halogenated C1-6 alkyl group, and
(iii) a cyano group,
(5) a 3- to 14-membered non-aromatic heterocyclic group,
(6) a C1-6 alkyl-carbonyl group,
(7) a C1-6 alkoxy group,
(8) a C1-6 alkoxy-carbonyl group,
(9) a carbamoyl group,
(10) a cyano group, and
(11) a halogen atom;
R5a and R6a are each independently a hydrogen atom or a C1-6 alkyl group;
R5b and R6b are both hydrogen atoms, or R5b and R6b together (i) form a double bond or (ii) form a C3-4 cycloalkyl including the carbon atom to which they are mutually bound;
and
either R7 or R8 is a hydrogen atom, and the other is a substituent, wherein the substituent is
(I) a C6-14 aryl group optionally having 1 to 3 substituents selected from the following (i) to (xvii):
(i) a halogen atom,
(ii) a cyano group,
(iii) a hydroxy group,
(iv) a C1-6 alkoxy group optionally having 1 to 3 substituents selected from a halogen atom, a C1-6 alkoxy group, a mono- or di-C1-6 alkyl-amino group and a C3-10 cycloalkyl group,
(v) a 5- to 14-membered aromatic heterocyclyloxy group,
(vi) a 3- to 14-membered non-aromatic heterocyclic group optionally having 1 to 5 halogen atoms,
(vii) a 5- to 14-membered aromatic heterocyclic group optionally having 1 to 3 optionally halogenated C1-6 alkyl groups,
(viii) a 3- to 14-membered non-aromatic heterocyclyl-carbonyl group,
(ix) a C1-6 alkoxy-carbonyl group,
(x) a carbamoyl group,
(xi) a C1-6 alkylsulfonyl group,
(xii) a C1-6 alkyl-carbonylamino group,
(xiii) a (C1-6 alkyl)(C1-6 alkyl-carbonyl)amino group,
(xiv) a C1-6 alkylsulfonylamino group,
(xv) a sulfamoyl group,
(xvi) a C3-10 cycloalkyl group, and
(xvii) a C1-6 alkyl group optionally having 1 to 7 substituents selected from the following (1) to (10):
(1) a halogen atom,
(2) a cyano group,
(3) a hydroxy group,
(4) a 3- to 14-membered non-aromatic heterocyclic group optionally having 1 to 5 substituents selected from an optionally hydroxy group-substituted C1-6 alkyl group, a halogen atom, a hydroxy group, a carboxy group, a carbamoyl group, a C1-6 alkoxy group and an oxo group,
(5) an optionally halogenated C1-6 alkoxy group,
(6) a C1-6 alkylsulfonyl group,
(7) 2-oxa-7-azaspiro[3.5]nonyl or 2-oxa-6-azaspiro[3.3]heptanyl,
(8) a 5- to 14-membered aromatic heterocyclic group optionally having 1 to 3 substituents selected from an amino group and a C1-6 alkyl group,
(9) a 7- to 10-membered bridged heterocyclic group optionally having 1 to 3 C1-6 alkyl groups, and
(10) an amino group optionally mono- or di-substituted by a substituent selected from the following (a) to (f):
(a) a C1-6 alkyl-carbonyl group,
(b) a C1-6 alkoxy-carbonyl group,
(c) a C1-6 alkyl group optionally having 1 to 5 substituents selected from a halogen atom, a cyano group, a hydroxy group, a C1-6 alkoxy group, a carboxy group, a C1-6 alkylsulfonyl group, a C1-6 alkyl-carbonylamino group, a C1-6 alkyl-sulfamoyl group and a 3- to 14-membered non-aromatic heterocyclic group,
(d) an optionally halogenated C3-10 cycloalkyl group,
(e) a 5- to 14-membered aromatic heterocyclic group, and
(f) a 3- to 14-membered non-aromatic heterocyclic group optionally having 1 to 3 substituents selected from a C1-6 alkyl group and an oxo group;
(II) a 5- to 14-membered aromatic heterocyclic group optionally having 1 to 3 substituents selected from the following (i) to (iv):
(i) a carbamoyl group,
(ii) an optionally halogenated C1-6 alkyl group,
(iii) a C3-10 cycloalkyl-C1-6 alkyl group, and
(iv) a 3- to 14-membered non-aromatic heterocyclyl-C1-6 alkyl group;
(III) a 3- to 14-membered non-aromatic heterocyclic group optionally having 1 to 3 substituents selected from the following (i) to (viii):
(i) a halogen atom,
(ii) an oxo group,
(iii) a C1-6 alkyl group optionally having 1 to 5 substituents selected from a halogen atom, a hydroxy group and a C1-6 alkoxy group,
(iv) a C3-10 cycloalkyl-C1-6 alkyl group optionally having 1 to 5 halogen atoms,
(v) an optionally halogenated C1-6 alkyl-carbonyl group,
(vi) a C1-6 alkoxy-carbonyl group,
(vii) a C3-10 cycloalkyl-carbonyl group, and
(viii) a 3- to 14-membered non-aromatic heterocyclyl-carbonyl group optionally having 1 to 3 C1-6 alkyl groups;
(IV) a C6-14 aryl-C3-10 cycloalkyl group;
(V) a C7-16 aralkyl group optionally having 1 to 3 substituents selected from the following (i) to (iii):
(i) a cyano group,
(ii) an optionally hydroxy group-substituted C1-6 alkyl group, and
(iii) an optionally halogenated C1-6 alkoxy group;
(VI) a 5- to 14-membered aromatic heterocyclyl-C1-6 alkyl group;
(VII) a 3- to 14-membered non-aromatic heterocyclyl-C1-6 alkyl group optionally having 1 to 3 C1-6 alkyl groups;
or
(VIII) dihydroindenyl or tetrahydronaphthalenyl optionally having a substituent selected from a C1-6 alkyl group and an oxo group.

85 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/304,623Filed 16 Apr 2015
Priority: JP 2014-08692718 Apr 2014
Published: US 2017/0044132 A116 Feb 2017
Granted: 1 May 2018
Term ends: Not estimatedThe source records don’t support an estimate.

Classification33 codes

C07D 401/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61K 31/4439
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
A61K 31/444
Containing further heterocyclic ring systems: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
A61K 31/4545
Containing further heterocyclic ring systems: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine

Family

US 2017/0044132 A1Pre-grant publication · published 16 Feb 2017
US 9,957,251 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound capable of inhibiting CDK8 and/or CDK19 represented by the formula:

or a salt thereof, wherein
R1 is a hydrogen atom;
R2 is a hydrogen atom, a halogen atom, an amino group or a hydroxy group;
R3 is a hydrogen atom or a halogen atom;
R4 is a 5- or 6-membered monocyclic aromatic heterocyclic group or an 8- to 14-membered fused polycyclic aromatic heterocyclic group, optionally substituted by 1 to 3 substituents selected from the following substituents (1) to (11):
(1) a C1-6 alkyl group optionally having 1 to 7 halogen atoms,
(2) a C1-6 alkyl group substituted by 1 to 7 substituents selected from
(i) a hydroxy group,
(ii) an amino group,
(iii) a C1-6 alkoxy group,
(iv) an optionally halogenated C3-10 cycloalkyl group,
(v) a 5- to 14-membered aromatic heterocyclic group,
(vi) a 3- to 14-membered non-aromatic heterocyclic group,
(vii) a C1-6 alkoxy-carbonyl group, and
(viii) a carbamoyl group,
(3) a C3-10 cycloalkyl group,
(4) a C7-16 aralkyl group optionally substituted by 1 to 7 substituents selected from the following (i) to (iii):
(i) a halogen atom,
(ii) an optionally halogenated C1-6 alkyl group, and
(iii) a cyano group,
(5) a 3- to 14-membered non-aromatic heterocyclic group,
(6) a C1-6 alkyl-carbonyl group,
(7) a C1-6 alkoxy group,
(8) a C1-6 alkoxy-carbonyl group,
(9) a carbamoyl group,
(10) a cyano group, and
(11) a halogen atom;
R5a and R6a are each independently a hydrogen atom or a C1-6 alkyl group;
R5b and R6b are both hydrogen atoms, or R5b and R6b together (i) form a double bond or (ii) form a C3-4 cycloalkyl including the carbon atom to which they are mutually bound;
and
either R7 or R8 is a hydrogen atom, and the other is a substituent, wherein the substituent is
(I) a C6-14 aryl group optionally having 1 to 3 substituents selected from the following (i) to (xvii):
(i) a halogen atom,
(ii) a cyano group,
(iii) a hydroxy group,
(iv) a C1-6 alkoxy group optionally having 1 to 3 substituents selected from a halogen atom, a C1-6 alkoxy group, a mono- or di-C1-6 alkyl-amino group and a C3-10 cycloalkyl group,
(v) a 5- to 14-membered aromatic heterocyclyloxy group,
(vi) a 3- to 14-membered non-aromatic heterocyclic group optionally having 1 to 5 halogen atoms,
(vii) a 5- to 14-membered aromatic heterocyclic group optionally having 1 to 3 optionally halogenated C1-6 alkyl groups,
(viii) a 3- to 14-membered non-aromatic heterocyclyl-carbonyl group,
(ix) a C1-6 alkoxy-carbonyl group,
(x) a carbamoyl group,
(xi) a C1-6 alkylsulfonyl group,
(xii) a C1-6 alkyl-carbonylamino group,
(xiii) a (C1-6 alkyl)(C1-6 alkyl-carbonyl)amino group,
(xiv) a C1-6 alkylsulfonylamino group,
(xv) a sulfamoyl group,
(xvi) a C3-10 cycloalkyl group, and
(xvii) a C1-6 alkyl group optionally having 1 to 7 substituents selected from the following (1) to (10):
(1) a halogen atom,
(2) a cyano group,
(3) a hydroxy group,
(4) a 3- to 14-membered non-aromatic heterocyclic group optionally having 1 to 5 substituents selected from an optionally hydroxy group-substituted C1-6 alkyl group, a halogen atom, a hydroxy group, a carboxy group, a carbamoyl group, a C1-6 alkoxy group and an oxo group,
(5) an optionally halogenated C1-6 alkoxy group,
(6) a C1-6 alkylsulfonyl group,
(7) 2-oxa-7-azaspiro[3.5]nonyl or 2-oxa-6-azaspiro[3.3]heptanyl,
(8) a 5- to 14-membered aromatic heterocyclic group optionally having 1 to 3 substituents selected from an amino group and a C1-6 alkyl group,
(9) a 7- to 10-membered bridged heterocyclic group optionally having 1 to 3 C1-6 alkyl groups, and
(10) an amino group optionally mono- or di-substituted by a substituent selected from the following (a) to (f):
(a) a C1-6 alkyl-carbonyl group,
(b) a C1-6 alkoxy-carbonyl group,
(c) a C1-6 alkyl group optionally having 1 to 5 substituents selected from a halogen atom, a cyano group, a hydroxy group, a C1-6 alkoxy group, a carboxy group, a C1-6 alkylsulfonyl group, a C1-6 alkyl-carbonylamino group, a C1-6 alkyl-sulfamoyl group and a 3- to 14-membered non-aromatic heterocyclic group,
(d) an optionally halogenated C3-10 cycloalkyl group,
(e) a 5- to 14-membered aromatic heterocyclic group, and
(f) a 3- to 14-membered non-aromatic heterocyclic group optionally having 1 to 3 substituents selected from a C1-6 alkyl group and an oxo group;
(II) a 5- to 14-membered aromatic heterocyclic group optionally having 1 to 3 substituents selected from the following (i) to (iv):
(i) a carbamoyl group,
(ii) an optionally halogenated C1-6 alkyl group,
(iii) a C3-10 cycloalkyl-C1-6 alkyl group, and
(iv) a 3- to 14-membered non-aromatic heterocyclyl-C1-6 alkyl group;
(III) a 3- to 14-membered non-aromatic heterocyclic group optionally having 1 to 3 substituents selected from the following (i) to (viii):
(i) a halogen atom,
(ii) an oxo group,
(iii) a C1-6 alkyl group optionally having 1 to 5 substituents selected from a halogen atom, a hydroxy group and a C1-6 alkoxy group,
(iv) a C3-10 cycloalkyl-C1-6 alkyl group optionally having 1 to 5 halogen atoms,
(v) an optionally halogenated C1-6 alkyl-carbonyl group,
(vi) a C1-6 alkoxy-carbonyl group,
(vii) a C3-10 cycloalkyl-carbonyl group, and
(viii) a 3- to 14-membered non-aromatic heterocyclyl-carbonyl group optionally having 1 to 3 C1-6 alkyl groups;
(IV) a C6-14 aryl-C3-10 cycloalkyl group;
(V) a C7-16 aralkyl group optionally having 1 to 3 substituents selected from the following (i) to (iii):
(i) a cyano group,
(ii) an optionally hydroxy group-substituted C1-6 alkyl group, and
(iii) an optionally halogenated C1-6 alkoxy group;
(VI) a 5- to 14-membered aromatic heterocyclyl-C1-6 alkyl group;
(VII) a 3- to 14-membered non-aromatic heterocyclyl-C1-6 alkyl group optionally having 1 to 3 C1-6 alkyl groups;
or
(VIII) dihydroindenyl or tetrahydronaphthalenyl optionally having a substituent selected from a C1-6 alkyl group and an oxo group.

85 more elements

Facts

Application

15/304,623Filed 16 Apr 2015

Priority

JP 2014-08692718 Apr 2014

Published

US 2017/0044132 A116 Feb 2017

Granted

1 May 2018

Term ends

Not estimatedThe source records don’t support an estimate.

Classification33 codes

C07D 401/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61K 31/4439
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
A61K 31/444
Containing further heterocyclic ring systems: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
A61K 31/4545
Containing further heterocyclic ring systems: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine