US 2004/0073026 A1Published application

Cyclic protein tyrosine kinase inhibitors

AssigneeBristol-Myers Squibb Company

InventorsJagabandhu Das, Ramesh Padmanabha, Ping Chen, Derek J. Norris, Arthur M.P. Doweyko, Joel C. Barrish, John Wityak

Life of this patent

Estimating the term…

Abstract

Novel cyclic compounds and salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds in the treatment of protein tyrosine kinase-associated disorders such as immunologic and oncologic disorders.

Claims59

Dependent claims

A cyclic compound of the following formula I or a salt thereof:

622
where
Q is:
(1) a 5-membered heteroaryl ring;
(2) a 6-membered heteroaryl ring;
or
(3) an aryl ring;
optionally substituted with one or more groups R1;
Z is:
(1) a single bond;
(2) —R15C═CH—;
or
(3) —(CH2)m—, where m is 1 to 2;
X1 and X2 are each hydrogen, or together form ═O or ═S;
R1 is:
(1) hydrogen or R6,
where R6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Z1, Z2 and one or more groups Z3;
(2) —OH or —OR6;
(3) —SH or —SR6;
(4) —C(O)2H, —C(O)qR6, or —O—C(O)qR6, where q is 1 or 2;
(5) —SO3H or S(O)qR6;
(6) halo;
(7) cyano;
(8) nitro;
(9) —Z4—NR7R8;
(10) —Z4—N(R9)—Z5—NR10R11;
(11) —Z4—N(R12)—Z5—R6;
(12) —P(O)(OR6)2;
R2 and R3 are each independently:
(1) hydrogen or R6;
(2) —Z4—R6;
or
(3) —Z13—NR7R8;
R4and R5:
(1) are each independently hydrogen or R6;
(2) —Z4—N(R9)—Z5—NR10R11;
(3) —N(R9)Z4R6;
or
(4) together with the nitrogen atom to which they are attached complete a 3- to 8-membered saturated or unsaturated heterocyclic ring which is unsubstituted or substituted with Z1, Z2 and Z3, which heterocyclic ring may optionally have fused to it a benzene ring itself unsubstituted or substituted with Z1, Z2 and Z3;
R7, R8, R9, R10, R11 and R12:
(1) are each independently hydrogen or R6;
(2) R7 and R8 may together be alkylene, alkenylene or heteroalkyl, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which, they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
or
(3) any two of R9, R10 and R11 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
R13 is:
(1) cyano;
(2) nitro;
(3) —NH2;
(4) —NHOalkyl;
(5) —OH;
(6) —NHOaryl;
(7) —NHCOOalkyl;
(8) —NHCOOaryl;
(9) —NHSO2alkyl;
(10) —NHSO2aryl;
(11) aryl;
(12) heteroaryl;
(13) —Oalkyl;
or
(14) —Oaryl;
R14 is:
(1) —NO2;
(2) —COOalkyl;
or
(3) —COOaryl;
R15 is:
(1) hydrogen;
(2) alkyl;
(3) aryl;
(4) arylalkyl;
or
(5) cycloalkyl;
Z1, Z2 and Z3 are each independently:
(1) hydrogen or Z6, where Z6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl;
(ii) a group (i) which is itself substituted by one or more of the same or different groups (i);
or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (16) of the definition of Z1, Z2 and Z3;
(2) —OH or —OZ6;
(3) —SH or —SZ6;
(4) C(O)qH, —C(O)qZ6) or —O—C(O)qZ6;
(5) —SO3H, —S(O)qZ6;
or S(O)qN(Z9)Z6;
(6) halo;
(7) cyano;
(8) nitro;
(9) —Z4—NZ7Z8;
(10) —Z4—N(Z9)—Z5—NZ7Z8;
(11) —Z4—N(Z10)—Z5—Z6;
(12) —Z4—N(Z10)—Z5—H;
(13) oxo;
(14) —O—C(O)—Z6;
(15) any two of Z1, Z2, and Z3 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;
or
(16) any two of Z1, Z2, and Z3 may together be —O—(CH2)r—O—, Where r is 1 to 5, completing a 4- to 8-membered ring together with the atoms to which they are attached;
Z4 and Z5 are each independently:
(1) a single bond;
(2) —Z11—S(O)q—Z12—;
(3) —Z11—C(O)—Z12—;
(4) —Z11—C(S)—Z12—;
(5) —Z11—O—Z12—;
(6) —Z11—S—Z12—;
(7) —Z11—O—C(O)—Z12—;
or
(8) —Z11—C(O)—O—Z12—;
Z7, Z8, Z9 and Z10:
(1) are each independently hydrogen or Z6;
(2) Z7 and Z8 or Z6 and Z10, may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
or
(3) Z7 or Z8, together with Z9, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
Z11 and Z12 are each independently:
(1) a single bond;
(2) alkylene;
(3) alkenylene;
or
(4) alkynylene;
and
Z13 is:
(1) a single bond;
(2) —Z11—S(O)q—Z12—;
(3) —Z11—C(O)—Z12—;
(4) —Z11—C(S)—Z12—;
(5) —Z11—O—Z12—;
(6) —Z11—S—Z12—;
(7) —Z11—O—C(O)—Z12—;
(8) —Z11—C(O)—O—Z12—;
(9) —C(NR13)—;
(10) —C(CHR14)—;
or
(11) —C(C(R14)2)—.
providing that said compound is other than
(a) a compound of formula (i)
623
where
R1a is alkyl or —C(O)NHNH2;
R2a and R3a are independently hydrogen, alkyl, —C(O)-(alk);
and
R4a is hydrogen and R5a is aryl, alkyl-substituted aryl, halo-substituted aryl, aralkyl, cycloalkyl or amino;
Or R4a is alkyl and R5a is alkyl or aryl;
Or R4a and R5a together with the nitrogen atom to which they are bonded together from morpholino.
(b) a compound of formula (ii) or (iii)
624
where
X is oxygen or sulfur;
R1b is hydrogen, halogen, alkyl or haloalkyl,
R2b is hydrogen, alkyl, aryl, aralkyl, heterocycle, heterocyclealkyl
R3b is alkyl, aryl, aralkyl, heterocycle, heterocyclealkyl
R4b is hydrogen, alkyl, or aralkyl;
and
R5b is hydrogen, alkyl, aryl, aralkyl, heterocycle or heterocyclealkyl
(c) a compound of formula (iv)
625
where
R4d and R5d are independently hydrogen, alkyl, alkenyl, or phenyl;
R27 is hydrogen or alkyl;
(d) a compound of formula (v)
626
where
R3e is phenyl, pyridyl or pryimidinyl optionally substituted with halogen or alkyl;
R50 and R51 are each independently hydrogen, halogen or alkyl;
R52 and R53 are each independently hydrogen, halogen, alkyl or haloalkyl;
R54 and R56 are each independently hydrogen, halogen, alkyl, nitro or amino;
R55 is hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, or alkoxycarbonyl;
and
n is zero or 1.
(e) a compound of formula (vi)
627
where
R2f and R3f are independently hydrogen or alkyl
R4f is hydrogen or alkyl;
and
R5f is alkyl, cycloalkyl, aryl, alkyl-substituted aryl, haloalkyl-substituted aryl, halo-substituted aryl, alkoxy-substituted aryl, nitro-substituted aryl, aryl-substituted aryl, aralkyl, or heteroaryl;
or R4f and R5f together with the nitrogen atom to which they are bonded form a morpholino ring
(f) a compound of formula (vii)
628
where
R2g is H or —N═O;
R3g is H or alkyl;
R4g is H or alkyl;
and
R5g is alkyl, aryl, or aralkyl.
(g) a compound of formula (viii)
629
where
R1h is alkyl or haloalkyl;
and
R57 is alkyl, alkoxy, alkenyl, akenyloxy, alkynyl, alkynyloxy, cycloalkyl, cycloakenyl, cycloalkoxy, cycloalkenyloxy, or phenyl
(h) a compound of formula (ix)
630
where
R2i is hydrogen or alkyl;
R3i is —C(O)—NH-(alk);
and
R58 and R59 are independently hydrogen, alkyl or halogen.
(i) a compound of formula (x)
631
where
R5j is alkynyl;
and
R61 and R62 are independently alkoxy or haloalkoxy.
(j) a compound of formula (xi)
632
where
R1k is hydrogen, alkyl, aryl or aralkyl;
*R1k is alkyl, aryl or aralkyl;
R3k and R5k are independently alkyl, aryl or aralkyl.
(k) a compound of formula (xii)
633
where
R2m is hydrogen or alkyl;
and
R3m is the radical of an anthraquinone, phthalocyanine, formazan, nitroaryl, dioxazine, phenazine or stilbene dye stuff.
(l) a compound of formula (xiii)
634
where
R1n is aralkyl or -(alk)C(O)-(aryl);
R2n is hydrogen, alkyl, alkenyl, hydroxyalkyl;
and
R3n is aralkyl
(m) a compound of formula (xiv)
635
where
R2p and R3p are independently hydrogen, alkyl, alkenyl, alkoxy, —CHO, —C(O)-(alk), —COO—(alk), -(alky)—COO-(alk), alkylthioalkyl, or aryl;
and
R5p is optionally substituted phenyl.
(n) a compound of formula (xv), (xvi) or (xvii)
636
where
X is oxygen or sulfur;
R2q is hydrogen
R3q optionally substituted phenyl;
R4q is hydrogen;
R5q is optionally substituted phenyl;
R2r and R3r are each independently hydrogen, alkyl, or aralkyl;
R4r is hydrogen;
and
R5r is optionally substituted phenyl;
(o) a compound of formula (xviii)
637
where
X is oxygen or sulfur,
R2s is hydrogen;
R3s is optionally substituted phenyl;
R4s is hydrogen;
and
R5s is optionally substituted phenyl;
(p) a compound of formula
638
(q) a compound of the formula
639
(r) the compound
640

247 more elements

23 A method for the treatment of a protein tyrosine kinase-associated disorder, comprising the step of administering to a subject in need thereof an amount effective therefor of at least one compound of formula III or a salt thereof:

652
where
Q is:
(1) a 5-membered heteroaryl ring;
(2) a 6-membered heteroaryl ring;
or
(3) an aryl ring;
optionally substituted with one or more groups R1;
Z is:
(1) a single bond;
(2) —R15C═CH—;
or
(3) —(CH2)m—, where m is 1 to 2;
X3 is oxygen or sulfur;
R1 is:
(1) hydrogen or R6,
where R6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Z1, Z2 and one or more groups Z3;
(2) —OH or —OR6;
(3) —SH or —SR6;
(4) —C(O)2H, —C(O)qR6, or —O—C(O)qR6, where q is 1 or 2;
(5) —SO3H or —S(O)qR6;
(6) halo;
(7) cyano;
(8) nitro;
(9) —Z4—NR7R8;
(10) —Z4—N(R9)—Z5—NR10R11;
(11) —Z4—N(R12)—Z5—R6;
(12) —P(O)(OR6)2;
R2 and R3 are each independently:
(1) hydrogen or R6;
(2) —Z4—R6;
or
(3) —Z13—NR7R8;
R4 and R5:
(1) are each independently hydrogen or R6;
(2) —Z4—N(R9)—Z5—NR10R11;
(3) —N(R9)Z4R6;
or
(4) together with the nitrogen atom to which they are attached complete a 3- to 8-membered saturated or unsaturated heterocyclic ring which is unsubstituted or substituted with Z1, Z2 and Z3, which heterocyclic ring may optionally have fused to it a benzene ring itself unsubstituted or substituted with Z1, Z2 and Z3;
R7, R8, R9, R10, R11 and R12:
(1) are each independently hydrogen or R6;
(2) R7and R8 may together be alkylene, alkenylene or heteroalkyl, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
or
(3) any two of R9 R10 and R11 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
R13 is:
(1) cyano;
(2) nitro;
(3) —NH2;
(4) —NHOalkyl;
(5) —OH;
(6) —NHOaryl;
(7) —NHCOOalkyl;
(8) —NHCOOaryl;
(9) —NHSO2alkyl;
(10) —NHSO2aryl;
(11) aryl;
(12) heteroaryl;
(13) —Oalkyl;
or
(14) —Oaryl;
R14 is:
(1) —NO2;
(2) —COOalkyl;
or
(3) —COOaryl;
R15 is:
(1) hydrogen;
(2) alkyl;
(3) aryl;
(4) arylalkyl;
or
(5) cycloalkyl;
Z1 Z2 and Z3 are each independently:
(1) hydrogen or Z6, where Z6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl;
(ii) a group (i) which is itself substituted by one or more of the same or different groups (i);
or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (16) of the definition of Z1, Z2 and Z3;
(2) —OH or —OZ6;
(3) —SH or —SZ6;
(4) C(O)qH, —C(O)qZ6, or —O—C(O)qZ6;
(5) —SO3H, —S(O)qZ6;
or S(O)qN(Z9)Z6;
(6) halo;
(7) cyano;
(8) nitro;
(9) —Z4—NZ7Z8;
(10) —Z4—N(Z9)—Z5—NZ7Z8;
(11) —Z4—N(Z10)—Z5—Z6;
(12) —Z4—N(Z10)—Z5—H;
(13) oxo;
(14) —O—C(O)—Z6;
(15) any two of Z1, Z2, and Z3 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;
or
(16) any two of Z1, Z2, and Z3 may together be —O—(CH2)r—O—, where r is 1 to 5, completing a 4- to 8-membered ring together with the atoms to which they are attached;
Z4 and Z5 are each independently:
(1) a single bond;
(2) —Z11—S(O)q—Z12—;
(3) —Z11—C(O)—Z12—;
(4) —Z11—C(S)—Z12—;
(5) —Z11—O—Z12—;
(6) —Z11—S—Z12—;
(7) —Z11—O—C(O)—Z12—;
or
(8) —Z11—C(O)—O—Z12—;
Z7, Z8, Z9 and Z10:
(1) are each independently hydrogen or Z6;
(2) Z7 and Z8, or Z6 and Z10, may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
or
(3) Z7 or Z8, together with Z9, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
Z11 and Z12 are each independently:
(1) a single bond;
(2) alkylene;
(3) alkenylene;
or
(4) alkynylene;
and
Z13 is:
(1) a single bond;
(2) —Z11—S(O)q—Z12—;
(3) —Z11—C(O)—Z12—;
(4) —Z11—C(S)—Z12—;
(5) —Z11—O—Z12—;
(6) —Z11—S—Z12—;
(7) —Z11—O—C(O)—Z12—;
(8) —Z11—C(O)—O—Z12—;
(9) —C(NR13)—;
(10) —C(CHR14)—;
or
(11) —C(C(R14)2)—.
providing that said compound is other than
(a) a compound of formula (i)
653
where
R1a is alkyl or —C(O)NHNH2;
R2a and R3a are independently hydrogen, alkyl, —C(O)-(alk);
and
R4a is hydrogen and R5a is aryl, alkyl-substituted aryl, halo-substituted aryl, aralkyl, cycloalkyl or amino;
Or R4a is alkyl and R5a is alkyl or aryl;
Or R4a and R5a together with the nitrogen atom to which they are bonded together from morpholino.
(b) a compound of formula (ii) or (iii)
654
where
X is oxygen or sulfur;
R1b is hydrogen, halogen, alkyl or haloalkyl,
R2b is hydrogen, alkyl, aryl, aralkyl, heterocycle, heterocyclealkyl
R3b is alkyl, aryl, aralkyl, heterocycle, heterocyclealkyl
R4b is hydrogen, alkyl, or aralkyl;
and
R5b is hydrogen, alkyl, aryl, aralkyl, heterocycle or heterocyclealkyl;
(c) a compound of formula (vi)
655
where
R4d and R5d are independently hydrogen, alkyl, alkenyl, or phenyl;
R27 is hydrogen or alkyl;
or.
(d) the compound
656

153 more elements

A compound of formula II or salt thereof:

657
where
n is 1 or 2
X3 is oxygen or sulur;
A is selected from carbon and nitrogen;
B is selected from nitrogen, oxygen and sulfur
R1 is:
(1) hydrogen or R6,
where R6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Z1, Z2 and one or more (preferably, one or two) groups Z3;
(2) —OH or —OR6;
(3) —SH or —SR6;
(4) —C(O)2H, —C(O)qR6, or —O—C(O)qR6, where q is 1 or 2;
(5) —SO3H or —S(O)qR6;
(6) halo;
(7) cyano;
(8) nitro;
(9) —Z4—NR7R8;
(10) —Z4—N(R9)—Z5—NR10R11;
(11) —Z4—N(R12)—Z5—R6;
(12) —P(O)(OR6)2;
R2 and R3 are each independently:
(1) hydrogen or R6;
(2) —Z4—R6;
or
(3) —Z13—NR7R8;
R4 and R5:
(1) are each independently hydrogen or R6;
(2) —Z4—N(R9)—Z5—NR10R11;
(3) —N(R9)Z4R6;
or
(4) together with the nitrogen atom to which they are attached complete a 3- to 8-membered saturated or unsaturated heterocyclic ring which is unsubstituted or substituted with Z1, Z2 and Z3, which heterocyclic ring may optionally have fused to it a benzene ring itself unsubstituted or substituted with Z1, Z2 and Z3;
R7, R8, R9, R10, R11 and R12:
(1) are each independently hydrogen or R6;
(2) R7 and R8 may together be alkylene, alkenylene or heteroalkyl, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
or
(3) any two of R9, R10 and R11 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
R13 is:
(1) cyano;
(2) nitro;
(3) —NH2;
(4) —NHOalkyl;
(5) —OH;
(6) —NHOaryl;
(7) —NHCOOalkyl;
(8) —NHCOOaryl;
(9) —NHSO2alkyl;
(10) —NHSO2aryl;
(11) aryl;
(12) heteroaryl;
(13) —Oalkyl;
or
(14) —Oaryl;
R14 is:
(1) —NO2;
(2) —COOalkyl;
or
(3) —COOaryl;
R15 is:
(1) hydrogen;
(2) alkyl;
(3) aryl;
(4) arylalkyl;
or
(5) cycloalkyl;
Z1, Z2 and Z3 are each independently:
(1) hydrogen or Z6, where Z6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl;
(ii) a group (i) which is itself substituted by one or more of the same or different groups (i);
or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (16) of the definition of Z1, Z2 and Z3;
(2) —OH or —OZ6;
(3) —SH or —SZ6;
(4) C(O)qH, —C(O)qZ6, or —O—C(O)qZ6;
(5) —SO3H, —S(O)qZ6;
or S(O)qN(Z9)Z6;
(6) halo;
(7) cyano;
(8) nitro;
(9) —Z4—NZ7Z8;
(10) —Z4—N(Z9)—Z5—NZ7Z8;
(11) —Z4—N(Z10)—Z5—Z6;
(12) —Z4—N(Z10)—Z5—H;
(13) oxo;
(14) —O—C(O)—Z6;
(15) any two of Z1, Z2, and Z3 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;
or
(16) any two of Z1, Z2, and Z3 may together be —O—(CH2)r—O—, where r is 1 to 5, completing a 4- to 8-membered ring together with the atoms to which they are attached;
Z4 and Z5 are each independently:
(1) a single bond;
(2) —Z11—S(O)q—Z12—;
(3) —Z11—C(O)—Z12—;
(4) —Z11—C(S)—Z12—;
(5) —Z11—O—Z12—;
(6) —Z11—S—Z12—;
(7) —Z11—O—C(O)—Z12—;
or
(8) —Z11—C(O)—O—Z12—;
Z7, Z8 Z9 and Z10:
(1) are each independently hydrogen or Z6;
(2) Z7and Z8, or Z6 and Z10, may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2and Z3;
or
(3) Z7 or Z8, together with Z9, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
Z1, and Z12 are each independently:
(1) a single bond;
(2) alkylene;
(3) alkenylene;
or
(4) alkynylene;
and
Z13 is:
(1) a single bond;
(2) —Z11—S(O)q—Z12—;
(3) —Z11—C(O)—Z12—;
(4) —Z11—C(S)—Z12—;
(5) —Z11—O—Z12—;
(6) —Z11—S—Z12—;
(7) —Z11—O—C(O)—Z12—;
(8) —Z11—C(O)—O—Z12—;
(9) —C(NR13)—;
(10) —C(CHR14)—;
or
(11) —C(C(R14)2)—.
providing that said compound is other than
(1) a compound of formula (i)
658
where
R1a is alkyl or —C(O)NHNH2;
R2a and R3a are independently hydrogen, alkyl, —C(O)-(alk);
and
R4a is hydrogen and R5a is aryl, alkyl-substituted aryl, halo-substituted aryl, aralkyl, cycloalkyl or amino;
Or R4a is alkyl and R5a is alkyl or aryl;
Or R4a and R5a together with the nitrogen atom to which they are bonded together from morpholino.
(2) a compound of formula (vi)
659
where
R4d and R5d are independently hydrogen, alkyl, alkenyl, or phenyl;
R27 is hydrogen or alkyl;
(3) a compound of formula (vii)
660
where
R3e is phenyl, pyridyl or pryimidinyl optionally substituted with halogen or alkyl;
R50 and R51 are each independently hydrogen, halogen or alkyl;
R52 and R53 are each independently hydrogen, halogen, alkyl or haloalkyl;
R54 and R56 are each independently hydrogen, halogen, alkyl, nitro or amino;
R55 is hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, or alkoxycarbonyl;
and
n is zero or 1;
(4) a compound of formula (viii)
661
where
R2f and R3f are independently hydrogen or alkyl
R4f is hydrogen or alkyl;
and
R5f is alkyl, cycloalkyl, aryl, alkyl-substituted aryl, haloalkyl-substituted aryl, halo-substituted aryl, alkoxy-substituted aryl, nitro-substituted aryl, aryl-substituted aryl, aralkyl, or heteroaryl;
or R4f and R5f together with the nitrogen atom to which they are bonded form a morpholino ring
(5) a compound of formula (ix)
662
where
R2g is H or —N═O;
R3g is H or alkyl;
R4g is H or alkyl;
and
R5g is alkyl, aryl, or aralkyl.
(6) a compound of formula (x)
663
where
R1h is alkyl or haloalkyl;
and
R57 is alkyl, alkoxy, alkenyl, akenyloxy, alkynyl, alkynyloxy, cycloalkyl, cycloakenyl, cycloalkoxy, cycloalkenyloxy, or phenyl
(7) a compound of formula (xi)
664
where
R2i is hydrogen or alkyl;
R3i is —C(O)—NH-(alk);
and
R58 and R59 are independently hydrogen, alkyl or halogen.
(8) a compound of formula (xii)
665
where
R5j is alkynyl;
and
R61 and R62 are independently alkoxy or haloalkoxy;
(9) a compound of formula
666
(10) a compound of the formula
667

181 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/378,461Filed 3 Mar 2003
Priority: 15 Apr 1999
Published: 15 Apr 2004
Term ends: Not estimatedThe source records don’t support an estimate.

Classification37 codes

C07D 277/56
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 5/14
Drugs for disorders of the endocrine system: of the thyroid hormones, e.g. T3, T4
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…

Family

Application60/129,510Us provisional application · filed 15 Apr 1999
Application09/548,929Division · filed 13 Apr 2000
Application10/378,461Division · filed 3 Mar 2003
US 6,596,746 B1Related patent
US 7,091,223 B2Related patent
US 2004/0073026 A1This patent

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

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Abstract

A cyclic compound of the following formula I or a salt thereof:

622
where
Q is:
(1) a 5-membered heteroaryl ring;
(2) a 6-membered heteroaryl ring;
or
(3) an aryl ring;
optionally substituted with one or more groups R1;
Z is:
(1) a single bond;
(2) —R15C═CH—;
or
(3) —(CH2)m—, where m is 1 to 2;
X1 and X2 are each hydrogen, or together form ═O or ═S;
R1 is:
(1) hydrogen or R6,
where R6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Z1, Z2 and one or more groups Z3;
(2) —OH or —OR6;
(3) —SH or —SR6;
(4) —C(O)2H, —C(O)qR6, or —O—C(O)qR6, where q is 1 or 2;
(5) —SO3H or S(O)qR6;
(6) halo;
(7) cyano;
(8) nitro;
(9) —Z4—NR7R8;
(10) —Z4—N(R9)—Z5—NR10R11;
(11) —Z4—N(R12)—Z5—R6;
(12) —P(O)(OR6)2;
R2 and R3 are each independently:
(1) hydrogen or R6;
(2) —Z4—R6;
or
(3) —Z13—NR7R8;
R4and R5:
(1) are each independently hydrogen or R6;
(2) —Z4—N(R9)—Z5—NR10R11;
(3) —N(R9)Z4R6;
or
(4) together with the nitrogen atom to which they are attached complete a 3- to 8-membered saturated or unsaturated heterocyclic ring which is unsubstituted or substituted with Z1, Z2 and Z3, which heterocyclic ring may optionally have fused to it a benzene ring itself unsubstituted or substituted with Z1, Z2 and Z3;
R7, R8, R9, R10, R11 and R12:
(1) are each independently hydrogen or R6;
(2) R7 and R8 may together be alkylene, alkenylene or heteroalkyl, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which, they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
or
(3) any two of R9, R10 and R11 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
R13 is:
(1) cyano;
(2) nitro;
(3) —NH2;
(4) —NHOalkyl;
(5) —OH;
(6) —NHOaryl;
(7) —NHCOOalkyl;
(8) —NHCOOaryl;
(9) —NHSO2alkyl;
(10) —NHSO2aryl;
(11) aryl;
(12) heteroaryl;
(13) —Oalkyl;
or
(14) —Oaryl;
R14 is:
(1) —NO2;
(2) —COOalkyl;
or
(3) —COOaryl;
R15 is:
(1) hydrogen;
(2) alkyl;
(3) aryl;
(4) arylalkyl;
or
(5) cycloalkyl;
Z1, Z2 and Z3 are each independently:
(1) hydrogen or Z6, where Z6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl;
(ii) a group (i) which is itself substituted by one or more of the same or different groups (i);
or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (16) of the definition of Z1, Z2 and Z3;
(2) —OH or —OZ6;
(3) —SH or —SZ6;
(4) C(O)qH, —C(O)qZ6) or —O—C(O)qZ6;
(5) —SO3H, —S(O)qZ6;
or S(O)qN(Z9)Z6;
(6) halo;
(7) cyano;
(8) nitro;
(9) —Z4—NZ7Z8;
(10) —Z4—N(Z9)—Z5—NZ7Z8;
(11) —Z4—N(Z10)—Z5—Z6;
(12) —Z4—N(Z10)—Z5—H;
(13) oxo;
(14) —O—C(O)—Z6;
(15) any two of Z1, Z2, and Z3 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;
or
(16) any two of Z1, Z2, and Z3 may together be —O—(CH2)r—O—, Where r is 1 to 5, completing a 4- to 8-membered ring together with the atoms to which they are attached;
Z4 and Z5 are each independently:
(1) a single bond;
(2) —Z11—S(O)q—Z12—;
(3) —Z11—C(O)—Z12—;
(4) —Z11—C(S)—Z12—;
(5) —Z11—O—Z12—;
(6) —Z11—S—Z12—;
(7) —Z11—O—C(O)—Z12—;
or
(8) —Z11—C(O)—O—Z12—;
Z7, Z8, Z9 and Z10:
(1) are each independently hydrogen or Z6;
(2) Z7 and Z8 or Z6 and Z10, may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
or
(3) Z7 or Z8, together with Z9, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
Z11 and Z12 are each independently:
(1) a single bond;
(2) alkylene;
(3) alkenylene;
or
(4) alkynylene;
and
Z13 is:
(1) a single bond;
(2) —Z11—S(O)q—Z12—;
(3) —Z11—C(O)—Z12—;
(4) —Z11—C(S)—Z12—;
(5) —Z11—O—Z12—;
(6) —Z11—S—Z12—;
(7) —Z11—O—C(O)—Z12—;
(8) —Z11—C(O)—O—Z12—;
(9) —C(NR13)—;
(10) —C(CHR14)—;
or
(11) —C(C(R14)2)—.
providing that said compound is other than
(a) a compound of formula (i)
623
where
R1a is alkyl or —C(O)NHNH2;
R2a and R3a are independently hydrogen, alkyl, —C(O)-(alk);
and
R4a is hydrogen and R5a is aryl, alkyl-substituted aryl, halo-substituted aryl, aralkyl, cycloalkyl or amino;
Or R4a is alkyl and R5a is alkyl or aryl;
Or R4a and R5a together with the nitrogen atom to which they are bonded together from morpholino.
(b) a compound of formula (ii) or (iii)
624
where
X is oxygen or sulfur;
R1b is hydrogen, halogen, alkyl or haloalkyl,
R2b is hydrogen, alkyl, aryl, aralkyl, heterocycle, heterocyclealkyl
R3b is alkyl, aryl, aralkyl, heterocycle, heterocyclealkyl
R4b is hydrogen, alkyl, or aralkyl;
and
R5b is hydrogen, alkyl, aryl, aralkyl, heterocycle or heterocyclealkyl
(c) a compound of formula (iv)
625
where
R4d and R5d are independently hydrogen, alkyl, alkenyl, or phenyl;
R27 is hydrogen or alkyl;
(d) a compound of formula (v)
626
where
R3e is phenyl, pyridyl or pryimidinyl optionally substituted with halogen or alkyl;
R50 and R51 are each independently hydrogen, halogen or alkyl;
R52 and R53 are each independently hydrogen, halogen, alkyl or haloalkyl;
R54 and R56 are each independently hydrogen, halogen, alkyl, nitro or amino;
R55 is hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, or alkoxycarbonyl;
and
n is zero or 1.
(e) a compound of formula (vi)
627
where
R2f and R3f are independently hydrogen or alkyl
R4f is hydrogen or alkyl;
and
R5f is alkyl, cycloalkyl, aryl, alkyl-substituted aryl, haloalkyl-substituted aryl, halo-substituted aryl, alkoxy-substituted aryl, nitro-substituted aryl, aryl-substituted aryl, aralkyl, or heteroaryl;
or R4f and R5f together with the nitrogen atom to which they are bonded form a morpholino ring
(f) a compound of formula (vii)
628
where
R2g is H or —N═O;
R3g is H or alkyl;
R4g is H or alkyl;
and
R5g is alkyl, aryl, or aralkyl.
(g) a compound of formula (viii)
629
where
R1h is alkyl or haloalkyl;
and
R57 is alkyl, alkoxy, alkenyl, akenyloxy, alkynyl, alkynyloxy, cycloalkyl, cycloakenyl, cycloalkoxy, cycloalkenyloxy, or phenyl
(h) a compound of formula (ix)
630
where
R2i is hydrogen or alkyl;
R3i is —C(O)—NH-(alk);
and
R58 and R59 are independently hydrogen, alkyl or halogen.
(i) a compound of formula (x)
631
where
R5j is alkynyl;
and
R61 and R62 are independently alkoxy or haloalkoxy.
(j) a compound of formula (xi)
632
where
R1k is hydrogen, alkyl, aryl or aralkyl;
*R1k is alkyl, aryl or aralkyl;
R3k and R5k are independently alkyl, aryl or aralkyl.
(k) a compound of formula (xii)
633
where
R2m is hydrogen or alkyl;
and
R3m is the radical of an anthraquinone, phthalocyanine, formazan, nitroaryl, dioxazine, phenazine or stilbene dye stuff.
(l) a compound of formula (xiii)
634
where
R1n is aralkyl or -(alk)C(O)-(aryl);
R2n is hydrogen, alkyl, alkenyl, hydroxyalkyl;
and
R3n is aralkyl
(m) a compound of formula (xiv)
635
where
R2p and R3p are independently hydrogen, alkyl, alkenyl, alkoxy, —CHO, —C(O)-(alk), —COO—(alk), -(alky)—COO-(alk), alkylthioalkyl, or aryl;
and
R5p is optionally substituted phenyl.
(n) a compound of formula (xv), (xvi) or (xvii)
636
where
X is oxygen or sulfur;
R2q is hydrogen
R3q optionally substituted phenyl;
R4q is hydrogen;
R5q is optionally substituted phenyl;
R2r and R3r are each independently hydrogen, alkyl, or aralkyl;
R4r is hydrogen;
and
R5r is optionally substituted phenyl;
(o) a compound of formula (xviii)
637
where
X is oxygen or sulfur,
R2s is hydrogen;
R3s is optionally substituted phenyl;
R4s is hydrogen;
and
R5s is optionally substituted phenyl;
(p) a compound of formula
638
(q) a compound of the formula
639
(r) the compound
640

247 more elements

Facts

Application

10/378,461Filed 3 Mar 2003

Priority

15 Apr 1999

Published

15 Apr 2004

Term ends

Not estimatedThe source records don’t support an estimate.

Classification37 codes

C07D 277/56
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 5/14
Drugs for disorders of the endocrine system: of the thyroid hormones, e.g. T3, T4
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…

Family

Application60/129,510Us provisional application · filed 15 Apr 1999

Application09/548,929Division · filed 13 Apr 2000

Application10/378,461Division · filed 3 Mar 2003

US 6,596,746 B1Related patent

US 7,091,223 B2Related patent

US 2004/0073026 A1This patent

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