US 10,538,517 B2Granted

Quinolone derivatives as FGFR inhibitors

AssigneePrincipia Biopharma Inc.

InventorsKenneth Albert Brameld, Erik Verner

Life of this patent

Estimating the term…

Abstract

Compounds that are Fibroblast Growth Factor Inhibitors (FGFR) and are therefore useful for the treatment of diseases treatable by inhibition of FGFR are disclosed. Also disclosed are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

Claims23

Dependent claims

A compound of Formula (I):

wherein:
J is N or CH;
J′ is N or CR1 where R1 is hydrogen, halo, alkyl, or cycloalkyl;
Ar is phenyl or heteroaryl, each ring optionally substituted with one, two, three, or four substituents independently selected from alkyl, cycloalkyl, hydroxy, alkoxy, halo, haloalkyl, alkyl sulfonyl, haloalkoxy, and cyano;
R2 is hydrogen, alkyl, alkynyl, acyl, alkoxycarbonyl, haloalkyl, cycloalkyl optionally substituted with amino, alkylamino, dialkylamino, or hydroxyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkoxyalkyloxyalkyl, aminoalkyl, heterocyclyl (wherein heterocyclyl is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkyloxy, aminoalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl), heterocyclylalkyl (wherein the heterocyclyl ring in heterocyclylalkyl is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, acyl, hydroxy, alkoxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl), aralkyl, heteroaralkyl, phenyl, or heteroaryl (where phenyl, phenyl ring in aralkyl, heteroaryl ring in heteroaralkyl and heteroaryl are optionally substituted with one, two, or three substituents where two of the optional substituents are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano and one of the optional substituents is alkyl, cycloalkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl);
and
(i) Q is alkylene and X is —NRb—Y—C(CN)═CHRc;
or
(ii) Q is alkylene, substituted alkylene, heteroalkylene, substituted heteroalkylene, or alkylene-cycloalkylene-alkylene;
and
X is a group of formula (a), (b), (c), or (d):
wherein:
T, U, and V, are independently N or CH provided that at least one of T and U is nitrogen;
ring A is heterocycloamino;
bridged heterocycloamino, or spiroheterocycloamino;
rings B and C are independently azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, or imidazolidine;
ring D is azetidinyl, pyrrolidinyl, piperidinyl, bridged heterocycloamino, or spiro heterocycloamino;
ring E is 5- or 6-membered cycloalkylene, phenylene, or 5- or 6-membered heteroarylene;
R3, R4, R5, R6, R7, R8, R9, and R10 are independently hydrogen, alkyl, hydroxy, alkoxy, or halo;
and
R11 is hydrogen, alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, or cyano;
R12 is hydrogen, alkyl, cycloalkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, or cyano;
each Y is —CO— or —SO2—;
each Rb is hydrogen or alkyl;
and
each Rc is alkyl, alkoxyalkyloxyalkyl, cycloalkyl (optionally substituted with alkyl), 1-aminocycloalk-1-yl, substituted alkyl, heterocyclylalkyl, heterocyclyl (wherein the heterocyclyl in heterocyclylalkyl and heterocyclyl are each independently optionally substituted with one, two, or three substituents where two of the optional substituents are independently selected from alkyl, alkoxy, hydroxy, halo, amino, and oxo, and one of the optional substituent is alkyl, hydroxyalkyl, alkoxyalkyl, acyl, haloalkyl, alkylsulfonyl, alkoxycarbonyl, or heterocyclyl wherein the heterocyclyl is optionally substituted with one or two substitutents independently selected from alkyl, halo, hydroxy, or alkoxy), heteroaralkyl (wherein the heteroaryl ring is optionally substituted with one or two substituents independently selected from alkyl, amino, alkylamino, or dialkylamino), bridged heterocycloaminoalkyl or spiroheterocycloaminoalkyl (wherein each of the aforementioned ring is optionally substituted with one or two alkyl and further wherein the alkylene chain in bridged heterocycloaminoalkyl or spiroheterocycloaminoalkyl is attached to the nitrogen atom of the bridged heterocycloamino and spiroheterocycloamino group), or -(alkylene)-NR13R14 where R13 and R14 together with the nitrogen atom to which they are attached form
where one or two of X1, X2 and X3 are nitrogen and the rest are carbon and the ring is optionally substituted with one or two substituents independently selected from alkyl, haloalkyl, and halo;
and/or a pharmaceutically acceptable salt thereof;
provided that:
(1) when (i) ring E is 6-membered cycloalkylene, phenylene, or 6-membered heteroarylene or (ii) ring D is piperidinyl, then Q and —NRb—Y—C(CN)═CHRc are meta or para to each other;
(2) when ring A is piperidinyl, then Q and —Y—C(CN)═CRcRd are meta or para to each other;
(3) when ring A is piperazinyl, then Q and —Y—C(CN)═CHRc are para to each other;
and (4) when rings A and D are pyrrolidinyl or azetidinyl, then Q and —NRb—Y—C(CN)═CHRc or Q and —Y—C(CN)═CHRc are (1,3) to each other.

30 more elements

A compound selected from the group consisting of:

2-(3-(2-(6-(2-chlorophenyl)-2-((4-(diethylamino)butyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)piperidine-1-carbonyl)-4-methylpent-2-enenitrile;
2-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)piperazine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;
2-(4-(2-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)piperazine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;
N-(1-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)piperidin-4-yl)-2-cyano-4,4-dimethylpent-2-enamide;
2-(4-(3-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)propyl)piperazine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;
2-((3aR,6aS)-5-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-4,4-dimethylpent-2-enenitrile;
2-(4-(3-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)propyl)piperazine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;
2-(3-(2-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethoxy)azetidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;
2-(3-(2-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethoxy)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;
2-(3-(2-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethoxy)pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;
N-(4-(2-(6-(2-chlorophenyl)-2-((4-(diethylamino)butyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-methylpent-2-enamide;
2-(3-(2-(6-(2-chlorophenyl)-2-((4-(diethylamino)butyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)piperidine-1-carbonyl)-4-methylpent-2-enenitrile;
N-(3-(2-(6-(2-chlorophenyl)-2-((4-(diethylamino)butyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-methylpent-2-enamide;
2-cyano-N-(4-(2-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-((4-(diethylamino)butyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-4-methylpent-2-enamide;
2-cyano-N-(3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-((4-(diethylamino)butyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)phenyl)-4-methylpent-2-enamide;
2-cyano-N-(3-(2-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-((4-(diethylamino)butyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-4-methylpent-2-enamide;
2-cyano-N-(3-(2-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-4-methylpent-2-enamide;
2-cyano-N-(4-(2-(6-(3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-4,4-dimethylpent-2-enamide;
4-amino-2-cyano-N-(4-(2-(6-(3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-4-methylpent-2-enamide;
2-cyano-N-(3-(2-(6-(3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-4,4-dimethylpent-2-enamide;
4-amino-2-cyano-N-(3-(2-(6-(3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-4-methylpent-2-enamide;
N-(3-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4,4-dimethylpent-2-enamide;
4-amino-N-(3-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-methylpent-2-enamide;
N-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4,4-dimethylpent-2-enamide;
4-amino-N-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-methylpent-2-enamide;
N-(6-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)pyridin-2-yl)-2-cyano-4,4-dimethylpent-2-enamide;
4-amino-N-(6-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)pyridin-2-yl)-2-cyano-4-methylpent-2-enamide;
4-amino-2-cyano-N-(4-(2-(6-(3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)pyridin-2-yl)-4-methylpent-2-enamide;
2-cyano-N-(6-(2-(6-(3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)pyridin-2-yl)-4,4-dimethylpent-2-enamide;
4-amino-N-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)pyridin-2-yl)-2-cyano-4-methylpent-2-enamide;
4-amino-N-(5-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)pyridin-2-yl)-2-cyano-4-methylpent-2-enamide;
4-amino-2-cyano-N-(6-(2-(6-(3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)pyridin-2-yl)-4-methylpent-2-enamide;
N-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)pyridin-2-yl)-2-cyano-4,4-dimethylpent-2-enamide;
2-cyano-N-(4-(2-(6-(3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)pyridin-2-yl)-4,4-dimethylpent-2-enamide;
4-amino-2-cyano-N-(5-(2-(6-(3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)pyridin-2-yl)-4-methylpent-2-enamide;
4-amino-N-(3-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-N,4-dimethylpent-2-enamide;
N-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-ethoxy-4-methylpent-2-enamide;
N-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-methyl-4-morpholinopent-2-enamide;
N-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-methyl-4-(methyl(oxetan-3-yl)amino)pent-2-enamide;
N-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-(4-ethylpiperazin-1-yl)-4-methylpent-2-enamide;
N-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-methyl-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pent-2-enamide;
N-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enamide;
N-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-methyl-4-(methylamino)pent-2-enamide;
N-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-(dimethylamino)-4-methylpent-2-enamide;
4-amino-N-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-N,4-dimethylpent-2-enamide;
N-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-N,4-dimethyl-4-(methylamino)pent-2-enamide;
N-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-(dimethylamino)-N,4-dimethylpent-2-enamide;
N-(3-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-N,4-dimethyl-4-(methylamino)pent-2-enamide;
N-(3-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-(dimethylamino)-N,4-dimethylpent-2-enamide;
2-cyano-N-(5-(2-(6-(3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)pyridin-2-yl)-4,4-dimethylpent-2-enamide;
N-(3-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-ethoxy-4-methylpent-2-enamide;
N-(3-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-methyl-4-morpholinopent-2-enamide;
N-(3-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-methyl-4-(methyl(oxetan-3-yl)amino)pent-2-enamide;
N-(3-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-methyl-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pent-2-enamide;
N-(3-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enamide;
N-(3-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-(4-ethylpiperazin-1-yl)-4-methylpent-2-enamide;
N-(5-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)pyridin-2-yl)-2-cyano-4,4-dimethylpent-2-enamide;
N-(3-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-methyl-4-(methylamino)pent-2-enamide;
N-(3-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-(dimethylamino)-4-methylpent-2-enamide;
N-(3-(2-(2-amino-6-(2-chloro-3, 5-dimethoxyphenyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4,4-dimethylpent-2-enamide;
N-(3-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(ethylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4,4-dimethylpent-2-enamide;
N-(3-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-((2-hydroxy-2-methylpropyl)amino)-7-oxopyrido[2, 3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4,4-dimethylpent-2-enamide;
N-(3-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-(4-hydroxypiperidin-1-yl)-4-methylpent-2-enamide;
N-(3-((6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)phenyl)-2-cyano-4,4-dimethylpent-2-enamide;
N-(3-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4,4-dimethylpentanamide;
N-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-(4-hydroxypiperidin-1-yl)-4-methylpent-2-enamide;
N-(3-(2-(6-(2-chloro-5-methoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4,4-dimethylpent-2-enamide;
2-cyano-N-(3-(2-(6-(2,4-dichlorophenyl)-2-(methylamino)-7-oxopyrido[2, 3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-4,4-dimethylpent-2-enamide;
2-cyano-N-(3-(2-(6-(2, 5-dimethylphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-4,4-dimethylpent-2-enamide;
N-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-methyl-4-((3 S,5R)-3,4,5-trimethylpiperazin-1-yl)pent-2-enamide;
N-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enamide;
N-(3-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enamide;
N-(3-(2-(6-(5-chloro-2-methoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4,4-dimethylpent-2-enamide;
2-cyano-4,4-dimethyl-N-(3-(2-(2-(methylamino)-7-oxo-6-(o-tolyl)pyrido [2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)pent-2-enamide;
2-cyano-N-(3-(2-(6-(2-fluoro-3-methoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-4,4-dimethylpent-2-enamide;
2-cyano-N-(3-(2-(6-(2-fluoro-5-methoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-4,4-dimethylpent-2-enamide;
N-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)thiazol-2-yl)-2-cyano-4,4-dimethylpent-2-enamide;
N-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-((2-morpholinoethyl)amino)-7-oxopyrido[2, 3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4,4-dimethylpent-2-enamide;
N-(6-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-((2-morpholinoethyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)pyridin-3-yl)-2-cyano-4,4-dimethylpent-2-enamide;
N-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-3-methylbut-2-enamide;
N-(5-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)pyrazin-2-yl)-2-cyano-4,4-dimethylpent-2-enamide;
N-(tert-butyl)-3-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyanoacrylamide;
N-(tert-butyl)-3-(3-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyanoacrylamide;
2-cyano-N-(4-(2-(6-(2-fluoro-3,5-dimethoxyphenyl)-2-((2-morpholinoethyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-4,4-dimethylpent-2-enamide;
N-(tert-butyl)-3-(4-(3-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)propyl)phenyl)-2-cyanoacrylamide;
N-(tert-butyl)-3-(3-(3-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)propyl)phenyl)-2-cyanoacrylamide;
N-(2-chloro-4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-((2-morpholinoethyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)phenyl)-2-cyano-4,4-dimethylpent-2-enamide;
N-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-((2-morpholinoethyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)-3-fluorophenyl)-2-cyano-4,4-dimethylpent-2-enamide;
and
N-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-((2-morpholinoethyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethyl)-2-fluorophenyl)-2-cyano-4,4-dimethylpent-2-enamide;
an individual (E) or (Z) isomer thereof;
or a pharmaceutically acceptable salt of any of the above compounds including the individual (E) or (Z) isomer.

89 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/575,448Filed 18 May 2016 · us provisional application
Priority: 22 May 2015
Published: US 2018/0155340 A17 Jun 2018
Granted: 21 Jan 2020
Term ends: Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07D 471/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 31/519
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: ortho- or peri-condensed with heterocyclic rings
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 19/08
Drugs for skeletal disorders: for bone diseases, e.g. rachitism, Paget's disease

Family

Application62/165,526Us provisional application · filed 22 May 2015
US 2018/0155340 A1Pre-grant publication · published 7 Jun 2018
US 10,538,517 B2This patent

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

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Abstract

A compound of Formula (I):

wherein:
J is N or CH;
J′ is N or CR1 where R1 is hydrogen, halo, alkyl, or cycloalkyl;
Ar is phenyl or heteroaryl, each ring optionally substituted with one, two, three, or four substituents independently selected from alkyl, cycloalkyl, hydroxy, alkoxy, halo, haloalkyl, alkyl sulfonyl, haloalkoxy, and cyano;
R2 is hydrogen, alkyl, alkynyl, acyl, alkoxycarbonyl, haloalkyl, cycloalkyl optionally substituted with amino, alkylamino, dialkylamino, or hydroxyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkoxyalkyloxyalkyl, aminoalkyl, heterocyclyl (wherein heterocyclyl is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkyloxy, aminoalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl), heterocyclylalkyl (wherein the heterocyclyl ring in heterocyclylalkyl is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, acyl, hydroxy, alkoxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl), aralkyl, heteroaralkyl, phenyl, or heteroaryl (where phenyl, phenyl ring in aralkyl, heteroaryl ring in heteroaralkyl and heteroaryl are optionally substituted with one, two, or three substituents where two of the optional substituents are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano and one of the optional substituents is alkyl, cycloalkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl);
and
(i) Q is alkylene and X is —NRb—Y—C(CN)═CHRc;
or
(ii) Q is alkylene, substituted alkylene, heteroalkylene, substituted heteroalkylene, or alkylene-cycloalkylene-alkylene;
and
X is a group of formula (a), (b), (c), or (d):
wherein:
T, U, and V, are independently N or CH provided that at least one of T and U is nitrogen;
ring A is heterocycloamino;
bridged heterocycloamino, or spiroheterocycloamino;
rings B and C are independently azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, or imidazolidine;
ring D is azetidinyl, pyrrolidinyl, piperidinyl, bridged heterocycloamino, or spiro heterocycloamino;
ring E is 5- or 6-membered cycloalkylene, phenylene, or 5- or 6-membered heteroarylene;
R3, R4, R5, R6, R7, R8, R9, and R10 are independently hydrogen, alkyl, hydroxy, alkoxy, or halo;
and
R11 is hydrogen, alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, or cyano;
R12 is hydrogen, alkyl, cycloalkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, or cyano;
each Y is —CO— or —SO2—;
each Rb is hydrogen or alkyl;
and
each Rc is alkyl, alkoxyalkyloxyalkyl, cycloalkyl (optionally substituted with alkyl), 1-aminocycloalk-1-yl, substituted alkyl, heterocyclylalkyl, heterocyclyl (wherein the heterocyclyl in heterocyclylalkyl and heterocyclyl are each independently optionally substituted with one, two, or three substituents where two of the optional substituents are independently selected from alkyl, alkoxy, hydroxy, halo, amino, and oxo, and one of the optional substituent is alkyl, hydroxyalkyl, alkoxyalkyl, acyl, haloalkyl, alkylsulfonyl, alkoxycarbonyl, or heterocyclyl wherein the heterocyclyl is optionally substituted with one or two substitutents independently selected from alkyl, halo, hydroxy, or alkoxy), heteroaralkyl (wherein the heteroaryl ring is optionally substituted with one or two substituents independently selected from alkyl, amino, alkylamino, or dialkylamino), bridged heterocycloaminoalkyl or spiroheterocycloaminoalkyl (wherein each of the aforementioned ring is optionally substituted with one or two alkyl and further wherein the alkylene chain in bridged heterocycloaminoalkyl or spiroheterocycloaminoalkyl is attached to the nitrogen atom of the bridged heterocycloamino and spiroheterocycloamino group), or -(alkylene)-NR13R14 where R13 and R14 together with the nitrogen atom to which they are attached form
where one or two of X1, X2 and X3 are nitrogen and the rest are carbon and the ring is optionally substituted with one or two substituents independently selected from alkyl, haloalkyl, and halo;
and/or a pharmaceutically acceptable salt thereof;
provided that:
(1) when (i) ring E is 6-membered cycloalkylene, phenylene, or 6-membered heteroarylene or (ii) ring D is piperidinyl, then Q and —NRb—Y—C(CN)═CHRc are meta or para to each other;
(2) when ring A is piperidinyl, then Q and —Y—C(CN)═CRcRd are meta or para to each other;
(3) when ring A is piperazinyl, then Q and —Y—C(CN)═CHRc are para to each other;
and (4) when rings A and D are pyrrolidinyl or azetidinyl, then Q and —NRb—Y—C(CN)═CHRc or Q and —Y—C(CN)═CHRc are (1,3) to each other.

30 more elements

Facts

Application

15/575,448Filed 18 May 2016 · us provisional application

Priority

22 May 2015

Published

US 2018/0155340 A17 Jun 2018

Granted

21 Jan 2020

Term ends

Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07D 471/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 31/519
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: ortho- or peri-condensed with heterocyclic rings
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 19/08
Drugs for skeletal disorders: for bone diseases, e.g. rachitism, Paget's disease