US 12,767,660 B2 · Substituted pyrazolo[1,5-a]pyrimidines as sepiapterin reductase inhibitors

Abstract

A condensed heterocyclic compound has a sepiapterin reductase inhibitory action and is particularly useful for treatment of a pain. The condensed heterocyclic compound represented by Formula (I) below (R1 represents a hydrocarbon group or the like; R2 and R3 represent a hydrogen atom or the like; R4, X, and Y represent defined substituents), a tautomer or a pharmaceutically acceptable salt of the compound, or a solvate of any of these.

A compound of Formula (I):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein
R1 is a substitutable hydrocarbon;
R2 is a hydrogen atom or a substitutable C1-6 alkyl;
R3 is a hydrogen atom or a substitutable C1-6 alkyl;
R4 is a hydrogen atom, a substitutable hydrocarbon, or a substitutable heterocyclic group;
X is a hydrogen atom, a halogen atom, a hydroxy, a cyano, a substitutable amino, a substitutable hydrocarbon, a substitutable heterocyclic group, an acyl, or —CR5═NR6;
Y is a hydrogen atom, a halogen atom, a cyano, a substitutable hydrocarbon, a substitutable heterocyclic group, an acyl, or —CR7═NR8;
or
X and Y, together with the carbon atoms to which they are bonded, form a substitutable 5- to 7-membered ring;
R5 is a hydrogen atom or C1-6 alkyl;
R6 is a substitutable hydroxy;
R7 is a hydrogen atom or C1-6 alkyl;
R8 is a substitutable hydroxy;
with the provisos that:
if X is a hydrogen atom, Y is not a hydrogen atom;
and
if Y is a hydrogen atom, X is not a hydrogen atom,
wherein
the term “substitutable hyrocarbon” refers to a C1-6 alkyl, a C2-6 alkenyl, a C2-6 alkynyl, a C3-10 cycloalkyl, a C3-10 cycloalkenyl, a C6-14 aryl, or a C7-16 aralkyl, optionally having one or more substituents independently selected from among the below-described substituent group A1 or substituent group A2;
the term “substitutable C1-6 alkyl” refers to a C1-6 alkyl optionally having one or more substituents independently selected from among the below-described substituent group A1 or substituent group A2;
the term “substitutable heterocyclic group” refers to a heterocyclic group having 0 to 3 substituents independently selected from substituent group A1 or substituent group A2 as defined below;
the term “substitutable 5- to 7-membered ring” refers to a 5- to 7-membered non-aromatic heterocyclic ring which may be substituted with a C1-6 alkyl, a C3-6 cycloalkyl or a 4- to 10-membered non-aromatic heterocyclic group, each of which may in turn be substituted with one or more substituents independently selected from the substituent group F as defined below;
the term “substitutable amino” refers to an amino optionally having one or two substituents independently selected from the group consisting of a C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C6-14 aryl, C7-16 aralkyl, 5 to 14-membered aromatic heterocyclic group, 3- to 14-membered non-aromatic heterocyclic group, C1-6 alkyl-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, 5-to 14-membered aromatic heterocyclic carbonyl, 3- to 14-membered non-aromatic heterocyclic carbonyl, C1-6 alkoxy-carbonyl, carbamoyl, sulfamoyl, mono- or di-C1-6 alkyl-carbamoyl, mono- or di-C7-16 aralkyl-carbamoyl, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, and (di-C1-6 alkylamino)methylene, each of which may have one or more substituents independently selected from substituent group A1 or substituent group A2;
and
the term “substitutable hydroxy” refers to a hydroxy optionally having a substituent selected from the group consisting of a C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C6-14 aryl, C7-16 aralkyl, 5- to 14-membered aromatic heterocyclic group, 3- to 14-membered non-aromatic heterocyclic group, C1-6 alkyl-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, 5- to 14-membered aromatic heterocyclic carbonyl, 3- to 14-membered non-aromatic heterocyclic carbonyl, C1-6 alkoxy-carbonyl, carbamoyl, mono- or di-C1-6 alkyl-carbamoyl, mono- or di-C7-16 aralkyl-carbamoyl, C1-6 alkylsulfonyl, and C6-14 arylsulfonyl, each of which may have one or more substituents independently selected from substituent group A1 of substituent group A2;
wherein substituent Group A1 includes:
(1) halogen atom,
(2) nitro,
(3) cyano,
(4) oxo,
(5) hydroxy,
(6) C1-6 alkoxy substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(7) C6-14 aryloxy,
(8) C7-16 aralkyloxy,
(9) 5- to 14-membered aromatic heterocyclic oxy,
(10) 3- to 14-membered non-aromatic heterocyclic oxy,
(11) C1-6 alkyl-carbonyloxy substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(12) C6-14 aryl-carbonyloxy,
(13) C1-6 alkoxy-carbonyloxy substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(14) mono- or di-C1-6 alkyl-carbamoyloxy substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(15) C6-14 aryl-carbamoyloxy,
(16) 5- to 14-membered aromatic heterocyclic carbonyloxy,
(17) 3- to 14-membered non-aromatic heterocyclic carbonyloxy,
(18) C1-6 alkylsulfonyloxy substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(19) C6-14 arylsulfonyloxy,
(20) C1-6 alkylthio substitutable with one or more substituents independently selected from among the below described substituent group C1,
(21) 5- to 14-membered aromatic heterocyclic group,
(22) 3- to 14-membered non-aromatic heterocyclic group,
(23) formyl,
(24) carboxy,
(25) C1-6 alkyl-carbonyl substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(26) C6-14 aryl-carbonyl,
(27) 5- to 14-membered aromatic heterocyclic carbonyl,
(28) 3- to 14-membered non-aromatic heterocyclic carbonyl,
(29) C3-10 cycloalkylcarbonyl,
(30) C3-10 cycloalkenylcarbonyl,
(31) C1-6 alkoxy-carbonyl substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(32) C6-14 aryloxy-carbonyl,
(33) C7-16 aralkyloxy-carbonyl,
(34) carbamoyl,
(35) thiocarbamoyl,
(36) mono- or di-C1-6 alkyl-carbamoyl substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(37) C6-14 aryl-carbamoyl,
(38) 5- to 14-membered aromatic heterocyclic carbamoyl,
(39) 3- to 14-membered non-aromatic heterocyclic carbamoyl,
(40) (hydroxy)(C1-6 alkyl)-carbamoyl,
(41) (C1-6 alkoxy)(C1-6 alkyl)-carbamoyl,
(42) C1-6 alkylsulfonyl substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(43) C6-14 arylsulfonyl,
(44) 5- to 14-membered aromatic heterocyclic sulfonyl,
(45) C1-6 alkylsulfinyl substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(46) C6-14 arylsulfinyl,
(47) 5- to 14-membered aromatic heterocyclic sulfinyl,
(48) amino,
(49) mono- or di-C1-6 alkylamino substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(50) mono- or di-C6-14 arylamino,
(51) 5- to 14-membered aromatic heterocyclic amino,
(52) C7-16 aralkylamino,
(53) formylamino,
(54) C1-6 alkyl-carbonylamino substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(55) (C1-6 alkyl)(C1-6 alkyl-carbonyl)amino,
(56) C6-14 aryl-carbonylamino,
(57) C1-6 alkoxy-carbonylamino substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(58) C7-16 aralkyloxy-carbonylamino,
(59) C1-6 alkylsulfonylamino substitutable with one or more substitutents independently selected from among the below-described substituent group C1,
(60) C6-14 arylsulfonylamino,
(61) carbamoylamino,
(62) C1-6 alkyl substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(63) C2-6 alkenyl substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(64) C2-6 alkynyl,
(65) C3-10 cycloalkyl,
(66) C3-10 cycloalkenyl, and
(62) C6-14 aryl;
among (1) to (67) described above, groups having a 5- to 14-membered aromatic heterocyclic ring, a 3- to 14-membered non-aromatic heterocyclic ring, a C3-10 cycloalkane, and a C3-10 cycloalkene may be substituted with one or more substituents independently selected from among the below-described substituent group D1;
wherein substituent Group A2 includes:
(1) halogen atom,
(2) nitro,
(3) cyano,
(4) oxo,
(5) hydroxy,
(6) C1-6 alkoxy substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(7) C6-14 aryloxy,
(8) C7-16 aralkyloxy,
(9) 5- to 14-membered aromatic heterocyclic oxy group,
(10) 3- to 14-membered non-aromatic heterocyclic oxy group,
(11) C1-6 alkyl-carbonyloxy substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(12) C6-14 aryl-carbonyloxy,
(13) C1-6 alkoxy-carbonyloxy substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(14) mono- or di-C1-6 alkyl-carbamoyloxy substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(15) C6-14 aryl-carbamoyloxy,
(16) 5- to 14-membered aromatic heterocyclic carbonyloxy,
(17) 3- to 14-membered heterocyclic carbonyloxy,
(18) C1-6 alkylsulfonyloxy substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(19) C6-14 arylsulfonyloxy,
(20) C1-6 alkylthio substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(21) 5- to 14-membered aromatic heterocyclic group,
(22) 3- to 14-membered non-aromatic heterocyclic group,
(23) formyl,
(24) carboxy,
(25) C1-6 alkyl-carbonyl substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(26) C6-14 aryl-carbonyl,
(27) 5 to 14-membered aromatic heterocyclic carbonyl,
(28) 3- to 14-membered non-aromatic heterocyclic carbonyl,
(29) C3-10 cycloalkylcarbonyl,
(30) C3-10 cycloalkenylcarbonyl,
(31) C1-6 alkoxy-carbonyl substitutable with one or more substituents independently elected from among the below-described substituent group C1,
(32) C6-14 aryloxy-carbonyl,
(33) C7-16 aralkyloxy-carbonyl,
(34) carbamoyl,
(35) thiocarbamoyl,
(36) mono- or di-C1-6 alkyl-carbamoyl substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(37) C6-14 aryl-carbamoyl,
(38) 5- to 14-membered aromatic heterocyclic carbamoyl,
(39) 3- to 14-membered non-aromatic heterocyclic carbamoyl,
(40) (hydroxy)(C1-6 alkyl)-carbamoyl,
(41) (C1-6 alkoxy)(C1-6 alkyl)-carbamoyl,
(42) C1-6 alkylsulfonyl substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(43) C6-14 arylsulfonyl,
(44) 5- to 14-membered aromatic heterocyclic sulfonyl,
(45) C1-6 alkylsulfinyl substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(46) C6-14 arylsulfinyl,
(47) 5- to 14-membered aromatic heterocyclic sulfinyl,
(48) amino,
(49) mono- or di-C1-6 alkylamino substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(50) mono- or di-C6-14 arylamino,
(51) 5- to 14-membered aromatic heterocyclic amino,
(52) C7-16 aralkylamino,
(53) formylamino,
(54) C1-6 alkyl-carbonylamino substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(55) (C1-6 alkyl)(C1-6 alkyl-carbonyl)amino,
(56) C6-14 aryl-carbonylamino,
(57) C1-6 alkoxy-carbonylamino substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(58) C7-16 aralkyloxy-carbonylamino,
(59) C1-6 alkylsulfonylamino substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(60) C6-14 arylsulfonylamino,
(61) carbamoylamino,
(62) C1-6 alkyl substitutable with one or more substitutents independently selected from among the below-described substituent group C1,
(63) C2-6 alkenyl substitutable with one or more substituents independently selected from among the below-described substituent group C1,
(64) C2-6 alkynyl,
(65) C3-10 cycloalkyl,
(66) C3-10 cycloalkenyl, and
(67) C6-14 aryl,
(68) N—C1-6 alkyl-N—C3-10 cycloalkylcarbamoyl,
(69) N—C1-6 alkyl-N-3- to 14-membered non-aromatic heterocyclic carbamoyl group,
(70) N,N-di-C3-10 cycloalkylcarbamoyl,
(71) N,N-di-C1-6 alkycarbamoyl substitutable with one or more substituents independently selected from among the below-described substituent group C2,
(72) N—C1-6 alkylcarbamoyl substitutable with one or more substituents independently selected from among the below-described substituent group C2,
(73) C6-14 aryl-carbonyl substituted with one or more substituents independently selected from among the below described substituent group C2,
(74) 3- to 14-membered non-aromatic heterocyclic carbonyl amino, and
(75) C3-10 cycloalkylcarbonylamino;
in the substituent group A2, among substituents described in (1) to (75) above, groups having a 5- to 14-membered aromatic heterocyclic ring, a 3- to 14-membered non-aromatic heterocyclic ring, a C3-10 cycloalkane, and a C3-10 cycloalkene may be substituted with one or more substituents independently selected from among the below-described substituent group D2;
wherein substituent group B includes:
halogen atom,
nitro,
cyano,
hydroxy,
formyl,
carboxy,
carbamoyl,
thiocarbamoyl,
amino,
formylamino, and
carbamoylamino;
wherein substituent group C1 includes:
substituents constituting the aforementioned substituent group B,
C1-6 alkyl-carbonyloxy,
C1-6 alkoxy-carbonyloxy,
mono- or di-C1-6 alkyl-carbamoyloxy,
possibly halogenated C1-6 alkylsulfonyloxy,
possibly halogenated C1-6 alkyl-carbonyl,
C1-6 alkoxy-carbonyl,
possibly halogenated C1-6 alkylsulfonyl,
mono- or di-C1-6 alkylamino,
C1-6 alkyl-carbonylamino,
(C1-6 alkyl)(C1-6 alkyl-carbonyl)amino,
C1-6 alkoxy-carbonylamino, and
C1-6 alkylsulfonylamino;
wherein substituent group C2 includes:
substituents constituting the aforementioned substituent group C1,
C7-16 aralkyloxy,
possibly halogenated C1-6 alkoxy,
possibly halogenated C3-10 cycloalkyl,
4- to 10-membered non-aromatic heterocyclic group,
4- to 10-membered non-aromatic heterocyclic oxy,
C6-14 aryl, and
5- to 10-membered aromatic heterocyclic group substitutable with C1-6 alkyl;
wherein substituent group D1 includes:
halogen atom,
nitro,
cyano,
hydroxy,
formyl,
carboxy,
carbamoyl,
thiocarbamoyl,
amino,
formylamino,
carbamoylamino,
C1-6 alkyl-carbonyloxy,
C1-6 alkoxy-carbonyloxy,
mono- or di-C1-6 alkyl-carbamoyloxy,
possibly halogenated C1-6 alkylsulfonyloxy,
possibly halogenated C1-6 alkyl-carbonyl,
C1-6 alkoxy-carbonyl,
possibly halogenated C1-6 alkylsulfonyl,
mono- or di-C1-6 alkylamino,
C1-6 alkyl-carbonylamino,
(C1-6 alkyl)(C1-6 alkyl-carbonyl)amino,
C1-6 alkoxy-carbonylamino,
C1-6 alkylsulfonylamino,
possibly halogenated C1-6 alkyl group, and
C2-6 alkenyl;
wherein substituent group D2 includes:
substituents constituting the aforementioned substituent group C2,
possibly halogenated C1-6 alkyl,
C2-6 alkenyl,
C1-6 alkyl substituted with C1-6 alkoxy,
C1-6 alkyl substituted with hydroxy,
N,N-di-C1-6 alkylcarbamoyl, and
C1-6 alkyl substituted with possibly halogenated C3-10 cycloalkyl;
wherein substituent group E includes:
halogen atom,
possibly halogenated C1-6 alkoxy,
carbamoyl,
carboxy,
hydroxy,
amino,
carbamoylamino,
C1-6 alkyl-carbonyl,
C1-6 alkoxy-carbonyl, and
C7-16 aralkyloxy;
wherein substituent group F includes:
substituents constituting the aforementioned substituent group E,
4- to 7-membered non-aromatic heterocyclic group, and
possibly halogenated C1-6 alkyl.

252 more elements

Substituted pyrazolo[1,5-a]pyrimidines as sepiapterin reductase inhibitors

Life of this patent

Substituted pyrazolo[1,5-a]pyrimidines as sepiapterin reductase inhibitors

Life of this patent

Abstract

Claims31