US 8,163,756 B2Granted

Enzyme modulators and treatments

AssigneeDeciphera Pharmaceuticals, LLC

InventorsDaniel L. Flynn, Peter A. Petillo

Life of this patent

Estimating the term…

Abstract

Novel compounds and methods of using those compounds for the treatment of inflammatory conditions, hyperproliferative diseases, cancer, and diseases characterized by hyper-vascularization are provided. In a preferred embodiment, modulation of the activation state of p38 kinase protein, abl kinase protein, ber-abl kinase protein, braf kinase protein, VEGFR kinase protein, or PDGFR kinase protein comprises the step of contacting said kinase protein with the novel compounds.

Claims8

Dependent claims

A compound of the formula

wherein A2 is a bicyclic fused heteroaryl selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring of formula I;
and wherein indicates either a saturated or an unsaturated bond;
wherein each Z3 and Z5 may be independently attached to either of the rings making up the foregoing bicyclic structures;
A1 is R2-substituted monocyclic 5-membered ring heteroaryl;
D is a moiety of the formula
wherein E1 is phenyl;
wherein the symbol (***) is the point of attachment to the Y group of formula I;
X1 is selected from the group consisting of O, S, NR3, —C(═O)—, —O—(CH2)n—, —S—(CH2)n—, —NR3-(CH2)n—, —O—(CH2)q—O—, —O—(CH2)q—NR3-, —N(R3)-(CH2)q—N(R3)-, —(CH2)n—N(R4)-C(═O)—, —(CH2)n—N(R4)-C(═O)(CH2)n—, —(CH2)n—CO—N(R4)-, —(CH2)p—, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the E1 ring and the E2 ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)n—, —(CH2)q—, (CH2)p, C2-C5alkenyl, and C2-C5alkynyl moieties of X1 may be further substituted by one or more C1-C6alkyl;
X2 is a direct bond wherein E1 is directly linked to the Y group of formula I;
and wherein the E2 ring is Z5- and/or Z6-substituted pyridinyl, pyrimidinyl;
each Z2 is independently and individually selected from the group consisting of hydroxyl, hydroxyC1-C6alkyl, cyano, (R3)2N—, (R4)2N—, (R4)2NC1-C6alkyl, (R4)2NC2-C6alkylN(R4)-(CH2)n, (R4)2NC2-C6alkylO—(CH2)n, (R3)2N—C(═O)—, (R4)2N—C(═O)—, (R4)2N—CO—C1-C6alkyl, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3)2NSO2, (R4)2NSO2, —SO2R5-, —(CH2)nN(R4)C(O)R8, ═O, ═NOH, ═N(OR6), heteroarylC1-C6alkyl, heterocyclylC1-C6alkyl, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, heterocyclylaminoC1-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z2 moiety to the A2 ring of formula I;
in the event that Z2 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
each Z3 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyl, hydroxyC1-C6alkyl, cyano, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl, halogen, CF3, (R3)2N—, (R4)2N—, (R4)2NC1-C6alkyl, (R4)2NC2-C6alkylN(R4)-CH2)n, (R4)2NC2-C6alkylO—(CH2)n, —R8C(═O)—, (R4)2N—CO—C1-C6alkyl, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3)2NSO2, —SO2R3, SOR3, (R4)2NSO2, —SO2R4, —SOR4, —(CH2)nN(R4)C(O)R8, —C═(NOH)R6, —C═(NOR3)R6, heteroaryl, heterocyclyl, heteroarylC1-C6alkyl, heterocyclylC1-C6alkyl, heteroaryloxy, heterocyclyloxy, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylamino, heteroarylamino, heterocyclylamino, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, heterocyclylaminoC1-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z3 moiety to the A2 ring of formula I;
in the event that Z3 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
each Z4 is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4)2N—C2-C6alkyl, (R4)2N—C2-C6alkylN(R4)-C2-C6alkyl, (R4)2N—C2-C6alkyl-O—C2-C6alkyl, (R4)2N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO2R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4 moiety to the A2 ring for formula I;
in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
each Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3)2, —O—(CH2)q—N(R4)2, —N(R3)-(CH2)q—N(R4)2, —R5, —O—(CH2)q—O-Alkyl, —O—(CH2)q—N(R4)2, —N(R3)-(CH2)q—O-Alkyl, —N(R3)-(CH2)q—N(R4)2, —O—(CH2)q—R5, and —N(R3)-(CH2)q—R5;
each Z6 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroarylamino, and heterocyclylamino, (R3)2N—, —N(R3)COR8, (R4)2N—, —R5, —N(R4)COR8, —N(R3)SO2R6-, —CON(R3)2, —CON(R4)2, —COR5, and —SO2NHR4;
each R2 is selected from the group consisting of monocyclic heteroaryl, C1-C6alkyl, branched C3-C7alkyl, R19 substituted C3-C8-carbocyclyl wherein R19 is H or C1-C6alkyl, C1-C6-fluoroalkyl wherein the alkyl group is partially or fully fluorinated, phenyl wherein the phenyl group is optionally substituted by one or more fluorine substituents and chlorine;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C7-carbocyclyl, and phenyl;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, Z2, or Z3 moieties containing a R5 moiety;
each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, carbocyclyl, phenyl, phenyC1-C6lalkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3)2, N(R4)2, and R5;
each R10 is independently and individually selected from the group consisting of CO2H, CO2C1-C6alkyl, CO—N(R4)2, OH, C1-C6alkoxy, and —N(R4)2;
each R13 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, hydroxyC2-C7alkyl, C1-C6alkoxyC2-C7alkyl, (R4)2N—CO, (R4)2N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R4)2N—C2-C6alkyl, (R4)2N—C2-C6alkylN(R4)-(CH2)q, R5-C2-C6alkylN(R4)-(CH2)q, (R4)2N—C2-C6alkylO-(CH2)q, R5-C2-C6alkyl-O—(CH2)q, —(CH2)qN(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC2-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, and heterocyclylaminoC2-C6alkyl;
V, V1, and V2 are each independently O or represent two hydrogens connected to the methylene carbon to which the V, V1, or V2 is attached;
wherein two R3 or R4 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen atom, said moieties may cyclize to form a C3-C7 heterocyclyl ring;
n is 0-4;
p is 1-4;
q is 2-6;
r is 1;
and v is 1 or 2;
or a tautomer, diastereomer, geometric isomer, enantiomer, hydrate, or salt of any of the foregoing.

37 more elements

A compound of the formula

wherein A2 is selected from the group consisting of
wherein each Z3 and Z5 is independently attached to either aryl or heteroaryl ring of the A2 bicyclic ring;
wherein the symbol (**) denotes the attachment to the A1 moiety of formula I;
A1 is selected from the group consisting of
wherein the symbol (*) denotes the attachment to the NH moiety of formula I and the symbol (**) denotes the attachment to the A2 moiety of formula I;
D is selected from the group consisting of
wherein E1 is phenyl;
X1 is selected from the group consisting of O;
X2 is a direct bond wherein E1 is directly linked to the Y group of formula I;
each R2 is selected from the group consisting of monocyclic heteroaryl, C1-C6alkyl, branched C3-C7alkyl, R19 substituted C3-C8-carbocyclyl wherein R19 is H or C1-C6alkyl, C1-C6-fluoroalkyl wherein the alkyl group is partially or fully fluorinated, phenyl wherein the phenyl group is optionally substituted by one or more fluorine substituents and chlorine;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7 alkyl, C3-C7-carbocyclyl, and phenyl;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6 alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, R13, Z2, Z3, Z4, Z5, or A2 ring moieties containing a R5 moiety;
wherein each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, carbocyclyl, phenyl, phenylC1-C6lalkyl, heteroaryl or heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3)2, N(R4)2, and R5;
each R10 is independently and individually selected from the group consisting of CO2H, CO2C1-C6alkyl, CO—N(R4)2, OH, C1-C6alkoxy, and —N(R4)2;
each R13 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, hydroxyC2-C7alkyl, C1-C6alkoxyC2-C7alkyl, (R4)2N—CO, (R4)2N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R4)2N—C2-C6alkyl, (R4)2N—C2-C6alkylN(R4)-(CH2)q, R5-C2-C6alkylN(R4)-(CH2)q, (R4)2N—C2-C6alkylO-(CH2)q, R5-C2-C6alkyl-O—(CH2)q, —(CH2)qN(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC2-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, and heterocyclylaminoC2-C6alkyl;
V, V1, and V2 are each independently or represent two hydrogens connected to the methylene carbon to which the V, V1, or V2 is attached;
each Z2 is independently and individually selected from the group consisting of hydroxyl, hydroxyC1-C6alkyl, cyano, (R3)2N—, (R4)2N—, (R4)2NC1-C6alkyl, (R4)2NC2-C6alkylN(R4)-(CH2)n, (R4)2NC2-C6alkylO-(CH2)n, (R3)2N—C(═O)—, (R4)2N—C(═O)—, (R4)2N—CO—C1-C6alkyl, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3)2NSO2, (R4)2NSO2, —SO2R5-, —(CH2)nN(R4)C(O)R8, ═O, ═NOH, ═N(OR6), heteroarylC1-C6alkyl, heterocyclylC1-C6alkyl, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, heterocyclylaminoC1-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z2 moiety to the A2 ring of formula I;
in the event that Z2 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
each Z3 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyl, hydroxyC1-C6alkyl, cyano, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl, halogen, CF3, (R3)2N—, (R4)2N—, (R4)2NC1-C6alkyl, (R4)2NC2-C6alkylN(R4)-CH2)n, (R4)2NC2-C6alkylO—(CH2)n, R8CO—, (R4)2N—CO—C1-C6alkyl, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3)2NSO2, —SO2R3, SOR3, (R4)2NSO2, —SO2R4, —SOR4, —(CH2)nN(R4)C(O)R8, —C═(NOH)R6, —C═(NOR3)R6, heteroaryl, heterocyclyl, heteroarylC1-C6alkyl, heterocyclylC1-C6alkyl, heteroaryloxy, heterocyclyloxy, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylamino, heteroarylamino, heterocyclylamino, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, heterocyclylaminoC1-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z3 moiety to the A2 ring of formula I;
in the event that Z3 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
each Z4 is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4)2N—C2-C6alkyl, (R4)2N—C2-C6alkylN(R4)-C2-C6alkyl, (R4)2N—C2-C6alkyl-O—C2-C6alkyl, (R4)2N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO2R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4 moiety to the A2 ring for formula I;
in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3)2, —O—(CH2)q—N(R4)2, —N(R3)-(CH2)q—N(R4)2, —R5, —O—(CH2)q—O-Alkyl, —O—(CH2)q—N(R4)2, —N(R3)-(CH2)q—O-Alkyl, —N(R3)-(CH2)q—N(R4)2, —O—(CH2)q—R5, and —N(R3)-(CH2)q—R5;
each Z6 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroarylamino, and heterocyclylamino, (R3)2N—, —N(R3)COR8, (R4)2N—, —R5, —N(R4)COR8, —N(R3)SO2R6-, —CON(R3)2, —CON(R4)2, —COR5, and —SO2NHR4;
wherein two R3 or R4 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen atom, said moieties may cyclize to form a C3-C7 heterocyclyl ring;
n is 0-4;
p is 1-4;
q is 2-6;
and v is 1 or 2;
or a tautomer, diastereomer, geometric isomer, enantiomer, hydrate, or salt of any of the foregoing.

33 more elements

A compound selected from

1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea,
1-(3-tert-butyl-1-(1H-indol-5-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea,
1-(3-tert-butyl-1-(indolin-5-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea,
1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea,
1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea,
1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(5-chloropyridin-3-yloxy)phenyl)urea,
1-(3-tert-butyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea,
1-(3-tert-butyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea,
1-(3-tert-butyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea,
1-(3-cyclopentyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea,
1-(3-cyclopentyl-1-(2-oxo-1,2-dihydroquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea,
1-(3-tert-butyl-1-(2-(piperazin-1-yl)quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea,
1-(1-(2-(2-aminoethylamino)quinolin-6-yl)-3-tert-butyl-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea,
1-(3-tert-butyl-1-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea,
1-(3-tert-butyl-1-(2-(methylamino)quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea,
1-(3-tert-butyl-1-(2-(dimethylamino)quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea,
1-(1-(2-aminoquinolin-6-yl)-3-tert-butyl-1H-pyrazol-5-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea,
1-(3-tert-butyl-1-(3-carbamoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea,
1-(3-tert-butyl-1-(1-(methylcarbamoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea,
1-(1-(3-((2,3-dihydroxypropyl)carbamoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-tert-butyl-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea,
6-(3-tert-butyl-5-(3-(3-(pyridin-3-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,
1-(3-tert-butyl-1-(3-(methylcarbamoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea, and
1-(1-(1-((2,3-dihydroxypropyl)carbamoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea.

20 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/963,740Filed 21 Dec 2007 · continuation
Priority: 23 Dec 2004
Published: US 2008/0113967 A115 May 2008
Granted: 24 Apr 2012
Term ends: Not estimatedThe source records don’t support an estimate.

Classification42 codes

C07D 231/40
Nitrogen atoms: acylated on said nitrogen atom
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 7/08
Drugs for disorders of the blood or the extracellular fluid: plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for…
A61P 9/00
Drugs for disorders of the cardiovascular system

Family

Application60/639,087Us provisional application · filed 23 Dec 2004
Application60/638,986Us provisional application · filed 23 Dec 2004
Application60/638,987Us provisional application · filed 23 Dec 2004
Application60/638,968Us provisional application · filed 23 Dec 2004
Application11/318,399Parent of this continuation · filed 23 Dec 2005
US 2008/0113967 A1Pre-grant publication · published 15 May 2008
US 2007/0078121 A1Published application
US 8,163,756 B2This patent

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

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Abstract

A compound of the formula

wherein A2 is a bicyclic fused heteroaryl selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the A1 ring of formula I;
and wherein indicates either a saturated or an unsaturated bond;
wherein each Z3 and Z5 may be independently attached to either of the rings making up the foregoing bicyclic structures;
A1 is R2-substituted monocyclic 5-membered ring heteroaryl;
D is a moiety of the formula
wherein E1 is phenyl;
wherein the symbol (***) is the point of attachment to the Y group of formula I;
X1 is selected from the group consisting of O, S, NR3, —C(═O)—, —O—(CH2)n—, —S—(CH2)n—, —NR3-(CH2)n—, —O—(CH2)q—O—, —O—(CH2)q—NR3-, —N(R3)-(CH2)q—N(R3)-, —(CH2)n—N(R4)-C(═O)—, —(CH2)n—N(R4)-C(═O)(CH2)n—, —(CH2)n—CO—N(R4)-, —(CH2)p—, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, and a direct bond wherein the E1 ring and the E2 ring are directly linked by a covalent bond;
and wherein the carbon atoms of —(CH2)n—, —(CH2)q—, (CH2)p, C2-C5alkenyl, and C2-C5alkynyl moieties of X1 may be further substituted by one or more C1-C6alkyl;
X2 is a direct bond wherein E1 is directly linked to the Y group of formula I;
and wherein the E2 ring is Z5- and/or Z6-substituted pyridinyl, pyrimidinyl;
each Z2 is independently and individually selected from the group consisting of hydroxyl, hydroxyC1-C6alkyl, cyano, (R3)2N—, (R4)2N—, (R4)2NC1-C6alkyl, (R4)2NC2-C6alkylN(R4)-(CH2)n, (R4)2NC2-C6alkylO—(CH2)n, (R3)2N—C(═O)—, (R4)2N—C(═O)—, (R4)2N—CO—C1-C6alkyl, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3)2NSO2, (R4)2NSO2, —SO2R5-, —(CH2)nN(R4)C(O)R8, ═O, ═NOH, ═N(OR6), heteroarylC1-C6alkyl, heterocyclylC1-C6alkyl, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, heterocyclylaminoC1-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z2 moiety to the A2 ring of formula I;
in the event that Z2 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
each Z3 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyl, hydroxyC1-C6alkyl, cyano, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl, halogen, CF3, (R3)2N—, (R4)2N—, (R4)2NC1-C6alkyl, (R4)2NC2-C6alkylN(R4)-CH2)n, (R4)2NC2-C6alkylO—(CH2)n, —R8C(═O)—, (R4)2N—CO—C1-C6alkyl, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3)2NSO2, —SO2R3, SOR3, (R4)2NSO2, —SO2R4, —SOR4, —(CH2)nN(R4)C(O)R8, —C═(NOH)R6, —C═(NOR3)R6, heteroaryl, heterocyclyl, heteroarylC1-C6alkyl, heterocyclylC1-C6alkyl, heteroaryloxy, heterocyclyloxy, heteroaryloxyC1-C6alkyl, heterocyclyloxyC1-C6alkyl, arylamino, heteroarylamino, heterocyclylamino, arylaminoC1-C6alkyl, heteroarylaminoC1-C6alkyl, heterocyclylaminoC1-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z3 moiety to the A2 ring of formula I;
in the event that Z3 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
each Z4 is a substituent attached to a ring nitrogen and is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4)2N—C2-C6alkyl, (R4)2N—C2-C6alkylN(R4)-C2-C6alkyl, (R4)2N—C2-C6alkyl-O—C2-C6alkyl, (R4)2N—CO—C2-C6alkyl, carboxyC2-C6alkyl, C1-C6alkoxycarbonylC2-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO2R8, —COR8, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, heterocyclylaminoC2-C6alkyl, and moieties of the formulae
wherein the symbol (#) indicates the point of attachment of the Z4 moiety to the A2 ring for formula I;
in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
each Z5 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, halogen, fluoroalkyl, cyano, hydroxyl, alkoxy, oxo, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino, —N(R3)2, —O—(CH2)q—N(R4)2, —N(R3)-(CH2)q—N(R4)2, —R5, —O—(CH2)q—O-Alkyl, —O—(CH2)q—N(R4)2, —N(R3)-(CH2)q—O-Alkyl, —N(R3)-(CH2)q—N(R4)2, —O—(CH2)q—R5, and —N(R3)-(CH2)q—R5;
each Z6 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, arylamino, heteroarylamino, and heterocyclylamino, (R3)2N—, —N(R3)COR8, (R4)2N—, —R5, —N(R4)COR8, —N(R3)SO2R6-, —CON(R3)2, —CON(R4)2, —COR5, and —SO2NHR4;
each R2 is selected from the group consisting of monocyclic heteroaryl, C1-C6alkyl, branched C3-C7alkyl, R19 substituted C3-C8-carbocyclyl wherein R19 is H or C1-C6alkyl, C1-C6-fluoroalkyl wherein the alkyl group is partially or fully fluorinated, phenyl wherein the phenyl group is optionally substituted by one or more fluorine substituents and chlorine;
each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C7-carbocyclyl, and phenyl;
each R4 is selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6 alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, carbocyclyl, hydroxyl substituted carbocyclyl, alkoxy substituted carbocyclyl, dihydroxy substituted carbocyclyl, phenyl, heteroaryl, heterocyclyl, phenylC1-C6alkyl, heteroarylC1-C6alkyl, and heterocyclylC1-C6alkyl;
each R5 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective R8, R10, Z2, or Z3 moieties containing a R5 moiety;
each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, phenyl, heteroaryl, and heterocyclyl;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, carbocyclyl, phenyl, phenyC1-C6lalkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, OH, C1-C6alkoxy, N(R3)2, N(R4)2, and R5;
each R10 is independently and individually selected from the group consisting of CO2H, CO2C1-C6alkyl, CO—N(R4)2, OH, C1-C6alkoxy, and —N(R4)2;
each R13 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, carbocyclyl, hydroxyC2-C7alkyl, C1-C6alkoxyC2-C7alkyl, (R4)2N—CO, (R4)2N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R4)2N—C2-C6alkyl, (R4)2N—C2-C6alkylN(R4)-(CH2)q, R5-C2-C6alkylN(R4)-(CH2)q, (R4)2N—C2-C6alkylO-(CH2)q, R5-C2-C6alkyl-O—(CH2)q, —(CH2)qN(R4)C(O)R8, aryl, arylC1-C6alkyl, heteroaryl, heteroarylC1-C6alkyl, heterocyclyl, heterocyclylC1-C6alkyl, aryloxyC2-C6alkyl, heteroaryloxyC2-C6alkyl, heterocyclyloxyC2-C6alkyl, arylaminoC2-C6alkyl, heteroarylaminoC2-C6alkyl, and heterocyclylaminoC2-C6alkyl;
V, V1, and V2 are each independently O or represent two hydrogens connected to the methylene carbon to which the V, V1, or V2 is attached;
wherein two R3 or R4 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen atom, said moieties may cyclize to form a C3-C7 heterocyclyl ring;
n is 0-4;
p is 1-4;
q is 2-6;
r is 1;
and v is 1 or 2;
or a tautomer, diastereomer, geometric isomer, enantiomer, hydrate, or salt of any of the foregoing.

37 more elements

Facts

Application

11/963,740Filed 21 Dec 2007 · continuation

Priority

23 Dec 2004

Published

US 2008/0113967 A115 May 2008

Granted

24 Apr 2012

Term ends

Not estimatedThe source records don’t support an estimate.

Classification42 codes

C07D 231/40
Nitrogen atoms: acylated on said nitrogen atom
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 7/08
Drugs for disorders of the blood or the extracellular fluid: plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for…
A61P 9/00
Drugs for disorders of the cardiovascular system

Family

Application60/639,087Us provisional application · filed 23 Dec 2004

Application60/638,986Us provisional application · filed 23 Dec 2004

Application60/638,987Us provisional application · filed 23 Dec 2004

Application60/638,968Us provisional application · filed 23 Dec 2004

Application11/318,399Parent of this continuation · filed 23 Dec 2005

US 2008/0113967 A1Pre-grant publication · published 15 May 2008

US 2007/0078121 A1Published application

US 8,163,756 B2This patent

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