US 2007/0185061 A1 · HETEROCYCLIC BORONIC ACID COMPOUNDS

Abstract

Dipeptidyl peptidase IV (DPP-IV)-inhibiting compounds are provided that have formula I: wherein n is 1 to 3; X is CH2; S; O; CF2 or C(CH3)2; Z is H; halogen; hydroxyl; (C1-6)alkoxy; (C1-12)alkyl; (C3-12)cycloalkyl; phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; optionally, X together with an adjacent ring carbon and Z form a fused cyclopropyl; and optionally, one of the bonds in the ring containing X is a double bond; and CRiRii, R1, R2, R3, R4 and R5 are as described herein.

A pyrrolidine compound of formula I:

including all enantiomers, diastereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof, wherein:
n is 1 to 3;
X is CH2;
S;
O;
CF2 or C(CH3)2;
Z is H;
halogen;
hydroxyl;
(C1-6)alkoxy;
(C1-12)alkyl;
(C3-12)cycloalkyl;
phenyl;
or heteroaryl;
where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
R7 is halogen;
(C1-10)alkyl;
(C1-10)alkoxy;
(C1-10)alkylamino;
(C1-10) dialkylamino;
benzyl;
benzyloxy;
hydroxyl(C1-6)alkyl;
hydroxymethyl;
nitro;
trifluoromethyl;
trifluoromethoxy;
trifluoromethylthio;
N-hydroxyamino;
cyano;
carboxy;
acetamido;
hydroxy;
sulfamoyl;
sulfonamido;
or carbamoyl;
optionally, X together with an adjacent ring carbon and Z form a fused cyclopropyl;
and
optionally, one of the bonds in the ring containing X is a double bond;
R1 and R2 independently or together are hydrogen;
a boronic acid protecting group;
or a group capable of being hydrolyzed to a hydroxyl group in an aqueous solution at physiological pH or in biological fluids;
and
CRiRii may be present or absent, and
when CRiRii is present, then
Ri, Rii, R3, R4 and R5 are selected from (aa) or (bb):
(aa) Ri, Rii, R3 and R4 are hydrogen;
and R5 is hydrogen, (C1-12)alkyl or (C3-12) cycloalkyl;
(bb) Ri, RiiR3, R4 and R5 are independently hydrogen;
alkyl;
alkenyl;
alkynyl;
cycloalkyl;
cycloalkylalkyl;
bicycloalkyl;
tricycloalkyl;
alkylcycloalkyl;
hydroxyalkyl;
hydroxyalkylcycloalkyl;
hydroxycycloalkyl;
hydroxybicycloalkyl;
hydroxytricycloalkyl;
bicycloalkylalkyl;
alkylbicycloalkyl;
alkylthioalkyl;
arylalkylthioalkyl;
cycloalkenyl;
aryl, aralkyl;
heteroaryl;
heteroarylalkyl;
cycloheteroalkyl or cycloheteroalkylalkyl;
all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl,
or alternatively,
when CRiRii is absent, then R3, R4 and R5 are selected from (cc), (dd) or (ee):
(cc) R3 and R4 are hydrogen;
and
R5 is
a) hydrogen, provided that R5 is not hydrogen when n is 1, X is CH2, and Z is H;
b) (C1-12)alkyl;
(C2-12)alkenyl;
(C2-12)alkynyl;
(C3-12)cycloalkyl;
or (C3-12)cycloalkenyl;
where the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- or independently plurisubstituted with R6, and where the alkyl, alkenyl, alkynyl portions include linear or branched chains and may include cyclic portions;
R6 is (C1-6)alkyl;
(C1-6)alkoxy;
cycloalkyl;
carboxy;
acetamido;
cyano;
nitro;
halogen;
hydroxy;
hydroxy(C1-6)alkyl;
hydroxymethyl;
trifluoromethyl;
trifluoromethoxy;
sulfamoyl;
sulfonamido;
carbamoyl;
aryl;
heteroaryl;
where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
amino, where the amino group is optionally mono- or independently plurisubstituted with R8;
—SOR8;
—SO2R8;
—COR8;
—CO2R8, —CONHR8;
—CON(R8)2;
—OR8;
or —S—R8;
R7 is halogen;
(C1-10)alkyl;
(C1-10)alkoxy;
(C1-10)alkylamino;
(C1-10) dialkylamino;
benzyl;
benzyloxy;
hydroxyl(C1-6)alkyl;
hydroxymethyl;
nitro;
trifluoromethyl;
trifluoromethoxy;
trifluoromethylthio;
N-hydroxyamino;
cyano;
carboxy;
acetamido;
hydroxy;
sulfamoyl;
sulfonamido;
or carbamoyl;
R8 is (C1-10)alkyl;
(C2-10)alkenyl;
(C2-10)alkynyl;
(C3-10)cycloalkyl;
(C5-10)cycloalkenyl;
benzyl;
phenethyl;
aryl;
or heteroaryl;
where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionally mono- or independently plurisubstituted with aryl or heteroaryl where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
c) aryl optionally fused to a (C3-10)cycloalkyl;
or heteroaryl optionally fused to a (C3-10)cycloalkyl;
where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
d) indanyl;
1,2,3,4-tetrahydronaphthyl;
(CH2)j adamantyl in which j is 0-3;
or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including (4-pentylbicyclo[2.2.2]oct-1-yl)amine;
where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH2)j adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- or independently plurisubstituted with hydroxy, (C1-8)alkyl, (C1-8)alkoxy, (C1-8)alkanoyloxy, or R9R10N—CO—O—, where R9 and R10 are independently (C1-8)alkyl, or phenyl, where the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C1-8)alkyl, (C1-8)alkoxy, halogen, or trifluoromethyl, or R9 and R10 together are (C3-6)alkylene;
e) R11(CH2)p— where R11 is 2-oxopyrrolidinyl;
(C1-6)alkoxy;
phenyl;
phenoxy;
(C1-8)cycloalkyl;
[3.3.3] bicyclic carbocyclic moiety;
pyridinyl;
naphthyl;
cyclohexenyl;
or adamantyl;
where the 2-oxopyrrolidinyl, (C1-6)alkoxy, phenyl, pyridinyl, and naphthyl groups are optionally mono- or independently di- or independently trisubstituted with R12;
where the phenoxy group is optionally mono- or independently disubstituted with (C1-4)alkyl, (C1-4)alkoxy, or halogen;
and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono- or independently plurisubstituted with (C1-8)alkyl;
and p is 0 to 3;
R12 is halogen;
trifluoromethyl;
cyano;
nitro;
(C1-6)alkyl;
(C1-6)alkoxy;
cycloalkyl;
carboxy;
acetamido;
hydroxy;
hydroxy(C1-6)alkyl;
hydroxymethyl;
trifluoromethoxy;
sulfamoyl;
carbamoyl;
sulfonamido;
alkylsufonyl;
phenylsulfonyl;
aryl;
heteroaryl;
where the aryl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7;
f) (R3)2CH(CH2)q—, where R13 is phenyl;
in which the phenyl groups are independently optionally mono- or independently disubstituted with R2;
and q is 0 to 3;
g) a group of the formula:
where R14 and R15 are independently hydrogen;
(C1-8)alkyl;
(C1-6)alkylcarbonyl;
(C3-12)cycloalkyl ring;
(C3-12)cycloalkenyl ring;
benzyl;
benzoyl;
pyridine;
pyrimidine;
phenyl;
phenylamino-carbonyl;
alkylsulfonyl;
or phenylsulfonyl;
where the cycloalkyl ring is optionally substituted with hydroxy(C1-6)alkyl, and where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12;
or R14 and R15 together form a (C3-12)cycloalkyl ring;
and r is 2 to 6;
h) a group of the formula:
where R16 and R17 are each independently hydrogen;
(C1-8)alkyl;
(C1-6)alkylcarbonyl;
di-(C1-6)alkylaminocarbonyl;
benzyl;
benzoyl;
pyridine;
pyrimidine;
phenyl;
phenylaminocarbonyl;
alkylsulfonyl;
or phenylsulfonyl;
where the benzyl, benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12;
or R16 and R17 together form a (C3-12)cycloalkyl ring;
and s is 1 to 6;
i) a group of the formula:
wherein R18 and R19 are independently hydrogen;
(C1-8)alkyl;
(C1-6)alkylcarbonyl;
di-(C1-6)alkylaminocarbonyl;
benzyl;
benzothiazole;
benzoyl;
pyridine;
pyrimidine;
phenyl;
phenylaminocarbonyl;
alkylsulfonyl;
or phenylsulfonyl;
where the benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or independently di-substituted with R12;
or wherein R18 and R19 together with the N form an (N, C3-12) heterocycloalkyl ring containing the nitrogen atom;
and each t is independently 0 to 6;
and u is 0 to 3;
j) a group of the formula:
(phenyl-CH2—C(CH3)2—),
where the phenyl group is optionally mono- or independently plurisubstituted with R12;
;
or
k) a group of the formula:
where R21 is hydrogen;
(C1-8)alkyl;
benzyl;
or phenyl;
in which the benzyl and phenyl groups are optionally mono- or independently di-substituted on the ring with R12;
each t is independently 0 to 6;
and u is 0 to 3;
and,
wherein a bond containing a wavy line signifies a point of attachment;
(dd) R3, R4 and R5 are independently hydrogen;
alkyl;
alkenyl;
alkynyl;
cycloalkyl;
cycloalkylalkyl;
bicycloalkyl;
tricycloalkyl;
alkylcycloalkyl;
hydroxyalkyl;
hydroxyalkylcycloalkyl;
hydroxycycloalkyl;
hydroxybicycloalkyl;
hydroxytricycloalkyl;
bicycloalkylalkyl;
alkylbicycloalkyl;
alkylthioalkyl;
arylalkylthioalkyl;
cycloalkenyl;
aryl or aralkyl;
all optionally mono- or independently plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, arylamino, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl, provided that when n is 1, X is CH2, the ring containing X is saturated, and Z, R3 and R5 are H, R4 is not a side chain of a naturally occurring α-amino acid, and provided that when n is 1, X is CH2, the ring containing X is saturated, and Z and R5 are H, R3 and R4 are not both methyl;
or,
(ee) R3 is hydrogen, and R4 and R5 together with the atoms to which they are attached form a 4 to 8 membered heterocyclic ring of 3 to 7 carbons and 1 nitrogen,
wherein the heterocyclic ring carbon atoms other than the carbon connected to N and R4 have the formula —(CR22R23)m— wherein m is 2 to 6, and R22 and R23 are independently hydrogen, hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, halo, amino, substituted amino, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, alkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, alkoxycarbonyl, aryloxycarbonyl, or alkylaminocarbonylamino;
and, optionally the heterocyclic ring has an aryl, heteroaryl or a 3 to 7 membered cycloalkyl ring fused thereto, provided that when n is 1, X is CH2, the ring containing X is saturated, and Z and R3 are H, then R4 and R5 together are not —(CH2)2— or —(CH2)3—.

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Heterocyclic boronic acid compounds

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Heterocyclic boronic acid compounds

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Abstract

Claims3