US 2014/0179694 A1Published application

Pyruvate kinase activators for use for increasing lifetime of the red blood cells and treating anemia

AssigneeAgios Pharmaceuticals, Inc.

InventorShin-San M. Su

Life of this patent

Estimating the term…

Abstract

Described herein are methods for using compounds that activate pyruvate kinase.

Claims72

Dependent claims

A method for increasing lifetime of the red blood cells (RBCs) in need thereof comprising contacting blood with an effective amount of (1) a compound of formula (I), (I-II), (I-III), or (I-IV) or a pharmaceutically acceptable salt thereof;

(2) a composition comprising a compound of formula (I), (I-II), (I-III), or (I-IV) or a salt thereof, and a carrier or (3) a pharmaceutically acceptable composition comprising a compound of formula (I), (I-II), (I-III), or (I-IV) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier:
formula (I):
wherein:
m is an integer from 0 to 5;
each R1 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-6 haloalkoxy, halo, acetyl, —NO2, aryl, aralkyl, heteroaryl, —SO2-aryl, —C(O)—NRb-aryl, —C(O)-aralkyl, —C(O)—C1-6 alkoxy, —NRb—SO2-aryl, wherein each aryl, aralkyl and heteroaryl group is optionally substituted with 0-3 occurrences of Rc and wherein two R1 groups taken together with the carbon atoms to which they are attached form a heterocyclyl ring;
n is an integer from 1 to 3;
each R2 is independently selected from C1-C6 alkyl and halo;
B is aryl, monocyclic heteroaryl, cycloalkyl, heterocyclyl, C1-6 aralkyl, or C1-6 heteroaralkyl;
L is a linker selected from —SO2—, —SO2NRa— and —NRaSO2—;
each Ra is independently selected from hydrogen and C1-C6 alkyl;
X and Y are each independently selected from O, S, NRb and CH2, wherein at least one of X and Y is O or S;
Z is O or S;
each Rb is independently selected from hydrogen, C1-6 aralkyl, and C1-C6 alkyl substituted with 0-1 occurrences of Rc;
and
Rc is independently selected from C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halo, NRdRd, and heterocyclyl and wherein two Rc groups taken together with the carbon atoms to which they are attached form a heterocyclyl ring;
and
Rd is independently selected from H and C1-6 alkyl;
formula (I-II):
wherein:
m is an integer from 0 to 5;
each R1 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-6 haloalkoxy, halo, acetyl, —NO2, aryl, aralkyl, heteroaryl, —SO2-aryl, —C(O)—NRb-aryl, —C(O)-aralkyl, —C(O)—C1-6 alkoxy, —NRb—SO2-aryl, wherein each aryl, aralkyl and heteroaryl group is optionally substituted with 0-3 occurrences of Rc and wherein two R1 groups taken together with the carbon atoms to which they are attached form a heterocyclyl ring;
n is an integer from 1 to 3;
each R2 is independently selected from C1-C6 alkyl and halo;
B is aryl, monocyclic heteroaryl, cycloalkyl, heterocyclyl, C1-6 aralkyl, or C1-6 heteroaralkyl;
L is a linker selected from —SO2—, —SO2NRa— and —NRaSO2—;
each Ra is independently selected from hydrogen and C1-C6 alkyl;
Z is O or S;
each Rb is independently selected from hydrogen, C1-6 aralkyl, and C1-C6 alkyl substituted with 0-1 occurrences of Rc;
and
Rc is independently selected from C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halo, NRdRd, and heterocyclyl and wherein two Rc groups taken together with the carbon atoms to which they are attached form a heterocyclyl ring;
and
Rd is independently selected from H and C1-6 alkyl;
formula (I-III):
wherein:
m is an integer from 0 to 5;
each R1 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-6 haloalkoxy, halo, acetyl, —NO2, aryl, aralkyl, heteroaryl, —SO2-aryl, —C(O)—NRb-aryl, —C(O)-aralkyl, —C(O)—C1-6 alkoxy, —NRb—SO2-aryl, wherein each aryl, aralkyl and heteroaryl group is optionally substituted with 0-3 occurrences of Rc and wherein two R1 groups taken together with the carbon atoms to which they are attached form a heterocyclyl ring;
each R2 is independently selected from C1-C6 alkyl and halo;
each Rb is independently selected from hydrogen, C1-6 aralkyl, and C1-C6 alkyl substituted with 0-1 occurrences of Rc;
Rc is independently selected from C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halo, NRdRd, and heterocyclyl and wherein two Rc groups taken together with the carbon atoms to which they are attached form a heterocyclyl ring;
and
Rd is independently selected from H and C1-6 alkyl;
formula (I-IV):
wherein:
m is an integer from 0 to 5;
each R1 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-6 haloalkoxy, halo, acetyl, —NO2, aryl, aralkyl, heteroaryl, —SO2-aryl, —C(O)—NRb-aryl, —C(O)-aralkyl, —C(O)—C1-6 alkoxy, —NRb—SO2-aryl, wherein each aryl, aralkyl and heteroaryl group is optionally substituted with 0-3 occurrences of Rc and wherein two R1 groups taken together with the carbon atoms to which they are attached form a heterocyclyl ring;
n is an integer from 0 to 3;
each R2 is independently selected from C1-C6 alkyl and halo;
B is aryl, monocyclic heteroaryl, cycloalkyl, heterocyclyl, C1-6 aralkyl, or C1-6 heteroaralkyl;
L is a linker selected from —SO2—, —SO2NRa— and —NRaSO2—;
each Ra is independently selected from hydrogen and C1-C6 alkyl;
X and Y are each independently selected from O, S, NRb and CH2;
Z is O or S;
each Rb is independently selected from hydrogen, C1-6 aralkyl, and C1-C6 alkyl substituted with 0-1 occurrences of Rc;
and
Rc is independently selected from C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halo, NRdRd, and heterocyclyl and wherein two Rc groups taken together with the carbon atoms to which they are attached form a heterocyclyl ring;
and
Rd is independently selected from H and C1-6 alkyl.

54 more elements

A method for increasing lifetime of the red blood cells (RBCs) in need thereof comprising contacting blood with an effective amount of (1) a compound of formula (II), (II-II), (II-III), (II-IV), (II-V), (II-VI), or (II-VII), or a pharmaceutically acceptable salt thereof;

(2) a composition comprising a compound of formula (II), (II-II), (II-III), (II-IV), (II-V), (II-VI), or (II-VII), or a salt thereof, and a carrier or (3) a pharmaceutically acceptable composition comprising a compound of formula (II), (II-II), (II-III), (II-IV), (II-V), (II-VI), or (II-VII), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier:
formula (II):
wherein
X1 is N or CE;
X2 is N or CD;
X3 is N or CB;
X4 is N or CA;
Y1, Y2, Y3 and Y4 are each independently selected from N and CR1;
A, B, D and E are each independently selected from H, R3 and —SO2—NR4R5;
wherein at least one of X1, X2, X3, X4, Y1, Y2, Y3 and Y4 is N;
and at least one of X1, X2, X3, X4, is C—SO2—NR4R5;
each R4 is independently selected from C1-8 alkyl, aryl and heteroaryl, each of which is substituted with n occurrences of R2;
each R5 is independently hydrogen or C1-8 alkyl;
each R1 is independently selected from hydrogen, C1-8 alkyl, C1-8 terminal alkynyl, C1-8 alkoxy, halogen, haloalkyl and haloalkoxy;
each R2 is independently selected from halo, haloalkyl, C1-4 alkyl, C2-4 alkenyl, C2-4 alknynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano, —ORa, —COORb and —CONRcRc′;
wherein two R2, together with the carbons to which they are attached, may form an optionally substituted ring, each of which can be further substituted;
each R3 is independently selected from C1-8 alkyl, —ORa, halogen, haloalkyl, haloalkoxy and optionally substituted heteroaryl;
each Ra is independently selected from alkyl, haloalkyl, optionally substituted heteroaryl and optionally substituted heterocyclyl;
each Rb is independently alkyl;
and
each Rc is independently selected from hydrogen and alkyl;
and
n is 0, 1, 2 or 3;
formula (II-II):
wherein
A, B, D and E are each independently selected from H, —SO2—NR4R5 and R3;
wherein at least one of A, B, D, or E is —SO2—NR4R5;
Y1, Y2, Y3 and Y4 are each independently selected from N and CR1, wherein at least one of Y1, Y2, Y3 and Y4 are N;
each R4 is independently selected from C1-8 alkyl, aryl and heteroaryl, each of which is substituted with n occurrences of R2;
each R5 is independently hydrogen or C1-8 alkyl;
each R1 is independently selected from hydrogen, C1-8 alkyl, C1-8 terminal alkynyl, C1-8 alkoxy, halogen, haloalkyl and haloalkoxy;
each R2 is independently selected from halo, haloalkyl, C1-4 alkyl, C2-4 alkenyl, C2-4 alknynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano, —ORa, —COORb and —CONRcRc′;
wherein two R2, together with the carbons to which they are attached, may form an optionally substituted ring, each of which can be further substituted;
each R3 is independently selected from C1-8 alkyl, —ORa, halogen, haloalkyl, haloalkoxy and optionally substituted heteroaryl;
each Ra is independently selected from alkyl, haloalkyl, optionally substituted heteroaryl and optionally substituted heterocyclyl;
each Rb is independently alkyl;
and
each Rc is independently selected from hydrogen and alkyl;
and
n is 0, 1, 2 or 3;
formula (II-III):
wherein
X1 is N or CE;
X2 is N or CD;
X3 is N or CB;
X4 is N or CA, wherein at least one of X1, X2, X3 and X4 is N and at least one of X1, X2, X3, X4, is C—SO2—NR4R5;
A, B, D and E are each independently selected from H, R3 and —SO2—NR4R5;
Y2 is selected from N and CR1;
each R4 is independently selected from C1-8 alkyl, aryl and heteroaryl, each of which is substituted with n occurrences of R2;
R5 is hydrogen or C1-8 alkyl;
each R1 is independently selected from hydrogen, C1-8 alkyl, C1-8 terminal alkynyl, C1-8 alkoxy, halogen, haloalkyl and haloalkoxy;
each R2 is independently selected from halo, haloalkyl, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano, —ORa, —COORb and —CONRcRc′;
wherein two R2, together with the carbons to which they are attached, may form an optionally substituted ring, each of which can be further substituted;
each R3 is independently selected from C1-8 alkyl, —ORa, halogen, haloalkyl, haloalkoxy and optionally substituted heteroaryl;
each Ra is independently selected from alkyl, haloalkyl, optionally substituted heteroaryl and optionally substituted heterocyclyl;
each Rb is independently alkyl;
and
each Rc is independently selected from hydrogen and alkyl;
and
n is 0, 1, 2 or 3;
formula (II-IV):
wherein
n is 0, 1, 2 or 3;
X1 is N or CE;
X2 is N or CD;
X3 is N or CB;
X4 is N or CA, wherein at least one of X1, X2, X3 and X4 is N;
and at least one of X1, X2, X3, X4, is C—SO2—NR4R5;
A, B, D and E are each independently selected from H and —SO2—NR4R5;
each R4 is independently selected from C1-8 alkyl, aryl and heteroaryl, each of which is substituted with n occurrences of R2;
each R5 is independently hydrogen or C1-8 alkyl;
each R1 is independently selected from hydrogen, C1-8 alkyl, C1-8 alkoxy, halogen, haloalkyl and haloalkoxy;
each R2 is independently selected from halo, haloalkyl, C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl heteroaryl, aryl, aralkyl, heteroaralkyl, cyano, —ORa, —COORb and —CONRcRc′;
wherein two R2, together with the carbons to which they are attached, may form an optionally substituted ring, each of which can be further substituted;
each R3 is independently selected from C1-8 alkyl, —ORa, halogen, haloalkyl, haloalkoxy or optionally substituted heteroaryl;
Ra is independently selected from alkyl, haloalkyl, optionally substituted heteroaryl and optionally substituted heterocyclyl;
each Rb is independently alkyl;
and
each Rc is independently selected from hydrogen and alkyl;
formula (II-V):
wherein
B, D and E are each independently selected from H and R3;
each R1 is independently selected from hydrogen, halo and haloalkyl;
R4 is hydrogen, C1-8 alkyl, and aryl, substituted with n occurrences of R2;
each R2 is independently selected from halo, haloalkyl, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano, —ORa, —COORb and —CONRcRc′;
wherein two R2, together with the carbons to which they are attached, may form an optionally substituted ring, each of which can be further substituted;
each R3 is independently selected from halo, haloalkyl and —ORa;
R5 is hydrogen or C1-8 alkyl;
Ra is independently selected from alkyl, haloalkyl, optionally substituted heteroaryl and optionally substituted heterocyclyl;
each Rb is independently alkyl;
each Rc is independently selected from hydrogen and alkyl;
and
n is 0, 1, 2 or 3;
formula (II-VI):
wherein
A, B and E are each independently selected from H, —SO2—NR4R5 and R3;
wherein at least one of A, B or E is —SO2—NR4R5;
Y1, Y2, Y3 and Y4 are each independently selected from N and CR1, wherein at least one of Y1, Y2, Y3 and Y4 are N;
each R4 is independently selected from C1-8 alkyl, aryl and heteroaryl, each of which is substituted with n occurrences of R2;
each R5 is independently hydrogen or C1-8 alkyl;
each R1 is independently selected from hydrogen, C1-8 alkyl, C1-8 terminal alkynyl, C1-8 alkoxy, halogen, haloalkyl and haloalkoxy;
each R2 is independently selected from halo, haloalkyl, C1-4 alkyl, C2-4 alkenyl, C2-4 alknynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano, —ORa, —COORb and —CONRcRc′;
wherein two R2, together with the carbons to which they are attached, may form an optionally substituted ring, each of which can be further substituted;
each R3 is independently selected from C1-8 alkyl, —ORa, halogen, haloalkyl, haloalkoxy and optionally substituted heteroaryl;
each Ra is independently selected from alkyl, haloalkyl, optionally substituted heteroaryl and optionally substituted heterocyclyl;
each Rb is independently alkyl;
and
each Rc is independently selected from hydrogen and alkyl;
and
n is 0, 1, 2 or 3;
formula (II-VII):
wherein
X1 is N or CE;
X2 is N or CD;
X3 is N or CB;
X4 is N or CA, wherein at least one of X1, X2, X3 and X4 is N and at least one of X1, X2, X3,
X4, is C—SO2—NR4R5;
A, B, D and E are each independently selected from H, R3 and —SO2—NR4R5;
Y1 is selected from N and CR1;
each R4 is independently selected from C1-8 alkyl, aryl and heteroaryl, each of which is substituted with n occurrences of R2;
R5 is hydrogen or C1-8 alkyl;
each R1 is independently selected from hydrogen, C1-8 alkyl, C1-8 terminal alkynyl, C1-8 alkoxy, halogen, haloalkyl and haloalkoxy;
each R2 is independently selected from halo, haloalkyl, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano, —ORa, —COORb and —CONRcRc′;
wherein two R2, together with the carbons to which they are attached, may form an optionally substituted ring, each of which can be further substituted;
each R3 is independently selected from C1-8 alkyl, —ORa, halogen, haloalkyl, haloalkoxy and optionally substituted heteroaryl;
each Ra is independently selected from alkyl, haloalkyl, optionally substituted heteroaryl and optionally substituted heterocyclyl;
each Rb is independently alkyl;
and
each Rc is independently selected from hydrogen and alkyl;
and
n is 0, 1, 2 or 3.

128 more elements

A method for increasing lifetime of the red blood cells (RBCs) in need thereof comprising contacting blood an effective amount of (1) a compound of formula (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof;

(2) a composition comprising a compound of formula (IV), (V), (VI), or (VII), or a salt thereof, and a carrier or (3) a pharmaceutically acceptable composition comprising a compound of formula (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier:
formula (IV):
or a pharmaceutically acceptable salt thereof, wherein:
X and Y are each independently selected from O and N(-L-R1);
Q is C(O), SO2, or —(CH2)h—;
each L is independently selected from a bond, —C(O)—, —(CRaRb)m—, —C(O)N(Rc)— or —C(O)O—;
D and D1 are each independently selected from a bond, O and N(Rc), provided that D and D1 are not both a bond;
A is aryl or heteroaryl, each of which is substituted with 0-3 occurrences of Rd;
and D-Q-D1-A is not OCH2-phenyl;
each R1 is independently selected from hydrogen, C1-4 alkyl, halo C1-4alkyl, alkyl-O-alkylene, C3-10 cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;
wherein each alkyl-O-alkylene, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl is substituted with 0-3 occurrences of Rf and each alkyl and haloalkyl is substituted with 0-3 occurrences of Rg;
each Ra and each Rb are independently selected from hydrogen, C1-4 alkyl, or Ra and Rb bound to the same carbon atom are taken together with the carbon atom to form a cycloalkyl;
each Rc is independently selected from hydrogen and C1-4 alkyl;
each Rd is independently selected from halo, halo C1-4 alkyl, C1-4 alkyl, nitro, cyano, —OH and —O(C1-4 alkyl), or two Rd, attached to the same or adjacent carbon atoms, taken together with the atom(s) to which they are attached form an optionally substituted heterocyclyl;
each Rf is independently selected from halo, halo C1-4alkyl, C1-4 alkyl, nitro, cyano, —OH and —O(C1-4 alkyl), or two Rf, attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl;
each Rg is independently selected from nitro, cyano, —OH, —O(C1-4 alkyl) or two Rg, attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl;
each R2 is independently selected from halo, halo C1-4 alkyl, C1-4 alkyl, C1-4 alkoxy and hydroxyl;
h is 1, 2 or 3;
each m is independently 1, 2 or 3;
and
each n is independently 0, 1, 2 or 3;
provided that the compound is not 2-chloro-N-(1,4-dihydro-2-oxo-2H-3,1-benzoxazin-7-yl)-5-[[(1-methylethyl)amino]sulfonyl]-benzamide;
4-[2-oxo-7-(phenylmethoxy)-2H-1,3-benzoxazin-3(4H)-yl], Benzoic methyl ester;
2-chloro-5-[[(1-methylethyl)amino]sulfonyl]-N-(1,2,3,4-tetrahydro-2-oxo-7-quinazolinyl)-benzamide;
or
2-chloro-5-[[(1-methylethyl)amino]sulfonyl]-N-(1,2,3,4-tetrahydro-3-methyl-2-oxo-7-quinazolinyl)-benzamide;
formula (V):
or a pharmaceutically acceptable salt thereof, wherein:
X and Y are each independently selected from O and N-L-R1;
Q is C(O), SO2, or —(CH2)h—;
each L is independently selected from a bond, —C(O)—, —(CRaRb)m—, —C(O)NRc— or —C(O)O—;
D and D1 are each independently selected from a bond, O and NRc, provided that D and D1 are not both a bond;
A is aryl or heteroaryl, each of which is substituted with 0-3 occurrences of Rd;
each R1 is independently selected from hydrogen, C1-4 alkyl, haloC1-4 alkyl, alkyl-O-alkylene, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;
wherein each alkyl-O-alkylene, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl is substituted with 0-3 occurrences of Rf and each alkyl and haloalkyl is substituted with 0-3 occurrences of Rg;
each Ra and each Rb are independently selected from hydrogen, C1-4 alkyl, or Ra and Rb bound to the same carbon atom are taken together with the carbon atom to form a cycloalkyl;
each Rc is independently selected from hydrogen and C1-4 alkyl;
each Rd is independently selected from halo, halo C1-4 alkyl, C1-4 alkyl, nitro, cyano, —OH and —O(C1-4 alkyl), or two Rd, attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl;
each Rf is independently selected from halo, halo C1-4 alkyl, C1-4 alkyl, nitro, cyano, —OH and —O(C1-4 alkyl), or two Rf, attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl;
each Rg is independently selected from nitro, cyano, —OH, —O(C1-4 alkyl) or two Rg, attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl;
each R2 is independently selected from halo, halo C1-4 alkyl, C1-4 alkyl, C1-4 alkoxy and hydroxyl;
h is 1, 2 or 3;
each m is independently 1, 2 or 3;
and
each n is independently 0, 1, 2 or 3;
provided that
1) D-Q-D1-A is not i) O-benzyl, ii) NHSO2-2-thiophenyl, iii) NHC(O)-optionally substituted phenyl, or iv) NHSO2-optionally substituted phenyl;
and
2) the compound is not:
i) N-(2,6-dimethylphenyl)-1,2,3,4-tetrahydro-1,3-dimethyl-2-oxo-6-Quinazolinesulfonamide;
ii) N-[2-[[[(1S)-2-cyclohexyl-1-methylethyl]amino]methyl]phenyl]-1,4-dihydro-2-oxo-2H-3,1-Benzoxazine-6-sulfonamide;
or
iii) N-[2-[[[(1S)-2-cyclopentyl-1-methylethyl]amino]methyl]phenyl]-1,4-dihydro-2-oxo-2H-3,1-Benzoxazine-6-sulfonamide;
formula (VI):
or a pharmaceutically acceptable salt thereof, wherein:
X and Y are each independently selected from O and N—R1;
Q is C(O), SO2, or —(CH2)h—;
L1 and L2 are each independently selected from a bond, —O—, C(O)—, —C(O)O—, —OC(O)—, —C(O)NRc—, —NRcC(O)—, —S—, —SO— and —SO2—;
D and D1 are each independently selected from a bond, O and NRc, provided that D and D1 are not both a bond;
A is aryl or heteroaryl, each of which is substituted with 0-3 occurrences of Rf;
each R1 is independently selected from hydrogen or C1-4 alkyl, wherein each C1-4 alkyl is substituted with 0-3 occurrences of Rf;
Ra and Rb are each independently selected from hydrogen, C1-4 alkyl, haloC1-4 alkyl, alkyl-O-alkylene, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;
wherein each alkyl-O-alkylene, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl is substituted with 0-3 occurrences of Rf and each alkyl and haloalkyl is substituted with 0-3 occurrences of Rg;
or
one of Ra or Rb is taken together with R1 and the atoms to which they are respectively attached to form an optionally substituted five-membered heterocyclyl;
each Rc is independently selected from hydrogen and C1-4 alkyl;
each Rd is independently selected from halo, halo C1-4 alkyl, C1-4 alkyl, nitro, —NRcRc, —NHCH(NRcRc)NRcRc, —NHC(═NRcRc)NRcRc, —C(O)NRcRc, cyano, —SRc and —ORc, or two Rd, attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl;
each Rf is independently selected from halo, halo C1-4 alkyl, C1-4 alkyl, nitro, cyano, —OH and —O(C1-4 alkyl), or two Rf, attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl;
each Rg is independently selected from nitro, cyano, —OH, —O(C1-4 alkyl) or two Rg, attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl;
each R2 is independently selected from halo, halo C1-4 alkyl, C1-4 alkyl, C1-4 alkoxy and hydroxyl;
h is 1, 2 or 3;
and
n is 0, 1, 2 or 3;
provided that
1) D-Q-D1-A is not —SO3-phenyl or —SO3-p-methylphenyl;
2) when Y is NRc, then Q is not C(O);
3) when Y is NH, D-Q-D1- is not SO2NRc or NRcSO2;
and
4) the compound is not:
i) N-(3-fluoro-2-methylphenyl)-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-6-sulfonamide;
ii) methyl 4,5-dimethoxy-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonamido)-phenethylcarbamate;
iii) 1-(difluoromethyl)-N-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-6-yl)-5-methyl-1H-pyrazole-4-sulfonamide;
iv) N-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-6-yl)-4-fluoro-3-methyl-benzenesulfonamide;
v) 7-chloro-N-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-6-yl)-2,3-dihydro-1,4-benzodioxin-6-sulfonamide;
vi) N-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-6-yl)-1,5-dimethyl-1H-pyrazole-4-sulfonamide;
vii) N-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-6-yl)-2-fluoro-5-methyl-benzenesulfonamide;
or
viii) 5-chloro-N-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-6-yl)-2,4-dimethoxy-benzenesulfonamide;
or
formula (VII):
or a pharmaceutically acceptable salt thereof, wherein:
X and Y are each independently selected from O and N—R1;
Q is C(O), SO2, or —(CH2)h—;
L1 and L2 are each independently selected from a bond, —O—, C(O)—, —C(O)O—, —OC(O)—, —C(O)NRc—, —NRcC(O)—, —S—, —SO— and —SO2—;
D and D1 are each independently selected from a bond, O and NRc, provided that D and D1 are not both a bond;
A is aryl or heteroaryl, each of which is substituted with 0-3 occurrences of Rd;
each R1 is independently selected from hydrogen or C1-4 alkyl;
wherein each C1-4 alkyl is substituted with 0-3 occurrences of Rf;
Ra and Rb are each independently selected from hydrogen, C1-4 alkyl, haloC1-4 alkyl, alkyl-O-alkylene, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocycloalkyl;
wherein each alkyl-O-alkylene, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl is substituted with 0-3 occurrences of Rf and each alkyl and haloalkyl is substituted with 0-3 occurrences of Rg;
or
one of Ra or Rb is taken together with a Y—R1 or X—R1 and the atoms to which they are respectively attached to form an optionally substituted five-membered heterocyclyl;
each Rc is independently selected from hydrogen and C1-4 alkyl;
each Rd is independently selected from halo, halo C1-4 alkyl, C1-4 alkyl, nitro, —NRcRc, —NHCH(NRcRc)NRcRc, —NHC(═NRcRc)NRcRc, —C(O)NRcRc, cyano, —SRc and —ORc, or two Rd, attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl;
each Rf is independently selected from halo, halo C1-4 alkyl, C1-4 alkyl, nitro, cyano, —OH and —O(C1-4 alkyl), or two Rf, attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl;
each Rg is independently selected from nitro, cyano, —OH, —O(C1-4 alkyl) or two Rg, attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl;
each R2 is independently selected from halo, halo C1-4 alkyl, C1-4 alkyl, C1-4 alkoxy and hydroxyl;
h is 1, 2 or 3;
and
n is 0, 1, 2 or 3;
provided that:
1) D-Q-D1-A is not O-benzyl;
2) when Y is O, X is not N—R1;
and
3) the compound of formula (IV) is not:
(E)-N-(3,3-dimethyl-2-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-4-(3,3,3-trifluoroprop-1-en-1-yl)benzamide;
(E)-N-(3,3-dimethyl-2-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-N-methyl-4-(3,3,3-trifluoroprop-1-en-1-yl)benzamide;
3-[2-(4-bromophenyl)-2-oxoethyl]-3,4-dihydro-6-methyl-2H-1,4-benzoxazin-2-one;
or
4-[[(3,4-dihydro-2-oxo-2H-1,4-benzoxazin-6-yl)amino]sulfonyl]-5-methyl-2-furancarboxylic acid ethyl ester.

117 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/115,286Filed 3 May 2012
Priority: 3 May 2011
Published: 26 Jun 2014
Term ends: Not estimatedThe source records don’t support an estimate.

Classification22 codes

C07D 413/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61K 31/385
Having sulfur as a ring hetero atom: having two or more sulfur atoms in the same ring
A61K 31/39
Having sulfur as a ring hetero atom: having oxygen in the same ring
A61K 31/423
Oxazoles: condensed with carbocyclic rings

Family

Application61/482,161Us provisional application · filed 3 May 2011
Application61/482,156Us provisional application · filed 3 May 2011
Application61/482,148Us provisional application · filed 3 May 2011
Application61/482,103Us provisional application · filed 3 May 2011
Application61/482,163Us provisional application · filed 3 May 2011
Application61/482,149Us provisional application · filed 3 May 2011
Application61/482,153Us provisional application · filed 3 May 2011
US 9,181,231 B2Related patent
US 2014/0179694 A1This patent

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

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

(2) a composition comprising a compound of formula (I), (I-II), (I-III), or (I-IV) or a salt thereof, and a carrier or (3) a pharmaceutically acceptable composition comprising a compound of formula (I), (I-II), (I-III), or (I-IV) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier:
formula (I):
wherein:
m is an integer from 0 to 5;
each R1 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-6 haloalkoxy, halo, acetyl, —NO2, aryl, aralkyl, heteroaryl, —SO2-aryl, —C(O)—NRb-aryl, —C(O)-aralkyl, —C(O)—C1-6 alkoxy, —NRb—SO2-aryl, wherein each aryl, aralkyl and heteroaryl group is optionally substituted with 0-3 occurrences of Rc and wherein two R1 groups taken together with the carbon atoms to which they are attached form a heterocyclyl ring;
n is an integer from 1 to 3;
each R2 is independently selected from C1-C6 alkyl and halo;
B is aryl, monocyclic heteroaryl, cycloalkyl, heterocyclyl, C1-6 aralkyl, or C1-6 heteroaralkyl;
L is a linker selected from —SO2—, —SO2NRa— and —NRaSO2—;
each Ra is independently selected from hydrogen and C1-C6 alkyl;
X and Y are each independently selected from O, S, NRb and CH2, wherein at least one of X and Y is O or S;
Z is O or S;
each Rb is independently selected from hydrogen, C1-6 aralkyl, and C1-C6 alkyl substituted with 0-1 occurrences of Rc;
and
Rc is independently selected from C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halo, NRdRd, and heterocyclyl and wherein two Rc groups taken together with the carbon atoms to which they are attached form a heterocyclyl ring;
and
Rd is independently selected from H and C1-6 alkyl;
formula (I-II):
wherein:
m is an integer from 0 to 5;
each R1 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-6 haloalkoxy, halo, acetyl, —NO2, aryl, aralkyl, heteroaryl, —SO2-aryl, —C(O)—NRb-aryl, —C(O)-aralkyl, —C(O)—C1-6 alkoxy, —NRb—SO2-aryl, wherein each aryl, aralkyl and heteroaryl group is optionally substituted with 0-3 occurrences of Rc and wherein two R1 groups taken together with the carbon atoms to which they are attached form a heterocyclyl ring;
n is an integer from 1 to 3;
each R2 is independently selected from C1-C6 alkyl and halo;
B is aryl, monocyclic heteroaryl, cycloalkyl, heterocyclyl, C1-6 aralkyl, or C1-6 heteroaralkyl;
L is a linker selected from —SO2—, —SO2NRa— and —NRaSO2—;
each Ra is independently selected from hydrogen and C1-C6 alkyl;
Z is O or S;
each Rb is independently selected from hydrogen, C1-6 aralkyl, and C1-C6 alkyl substituted with 0-1 occurrences of Rc;
and
Rc is independently selected from C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halo, NRdRd, and heterocyclyl and wherein two Rc groups taken together with the carbon atoms to which they are attached form a heterocyclyl ring;
and
Rd is independently selected from H and C1-6 alkyl;
formula (I-III):
wherein:
m is an integer from 0 to 5;
each R1 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-6 haloalkoxy, halo, acetyl, —NO2, aryl, aralkyl, heteroaryl, —SO2-aryl, —C(O)—NRb-aryl, —C(O)-aralkyl, —C(O)—C1-6 alkoxy, —NRb—SO2-aryl, wherein each aryl, aralkyl and heteroaryl group is optionally substituted with 0-3 occurrences of Rc and wherein two R1 groups taken together with the carbon atoms to which they are attached form a heterocyclyl ring;
each R2 is independently selected from C1-C6 alkyl and halo;
each Rb is independently selected from hydrogen, C1-6 aralkyl, and C1-C6 alkyl substituted with 0-1 occurrences of Rc;
Rc is independently selected from C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halo, NRdRd, and heterocyclyl and wherein two Rc groups taken together with the carbon atoms to which they are attached form a heterocyclyl ring;
and
Rd is independently selected from H and C1-6 alkyl;
formula (I-IV):
wherein:
m is an integer from 0 to 5;
each R1 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-6 haloalkoxy, halo, acetyl, —NO2, aryl, aralkyl, heteroaryl, —SO2-aryl, —C(O)—NRb-aryl, —C(O)-aralkyl, —C(O)—C1-6 alkoxy, —NRb—SO2-aryl, wherein each aryl, aralkyl and heteroaryl group is optionally substituted with 0-3 occurrences of Rc and wherein two R1 groups taken together with the carbon atoms to which they are attached form a heterocyclyl ring;
n is an integer from 0 to 3;
each R2 is independently selected from C1-C6 alkyl and halo;
B is aryl, monocyclic heteroaryl, cycloalkyl, heterocyclyl, C1-6 aralkyl, or C1-6 heteroaralkyl;
L is a linker selected from —SO2—, —SO2NRa— and —NRaSO2—;
each Ra is independently selected from hydrogen and C1-C6 alkyl;
X and Y are each independently selected from O, S, NRb and CH2;
Z is O or S;
each Rb is independently selected from hydrogen, C1-6 aralkyl, and C1-C6 alkyl substituted with 0-1 occurrences of Rc;
and
Rc is independently selected from C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halo, NRdRd, and heterocyclyl and wherein two Rc groups taken together with the carbon atoms to which they are attached form a heterocyclyl ring;
and
Rd is independently selected from H and C1-6 alkyl.

54 more elements

Facts

Application

14/115,286Filed 3 May 2012

Priority

3 May 2011

Published

26 Jun 2014

Term ends

Not estimatedThe source records don’t support an estimate.

Classification22 codes

C07D 413/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61K 31/385
Having sulfur as a ring hetero atom: having two or more sulfur atoms in the same ring
A61K 31/39
Having sulfur as a ring hetero atom: having oxygen in the same ring
A61K 31/423
Oxazoles: condensed with carbocyclic rings

Family

Application61/482,161Us provisional application · filed 3 May 2011

Application61/482,156Us provisional application · filed 3 May 2011

Application61/482,148Us provisional application · filed 3 May 2011

Application61/482,103Us provisional application · filed 3 May 2011

Application61/482,163Us provisional application · filed 3 May 2011

Application61/482,149Us provisional application · filed 3 May 2011

Application61/482,153Us provisional application · filed 3 May 2011

US 9,181,231 B2Related patent

US 2014/0179694 A1This patent

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