US 2004/0110752 A1Published application

Thiazolyl inhibitors of Tec family tyrosine kinases

AssigneeBristol-Myers Squibb Company

InventorsJoel C. Barrish, Jagabandhu Das, Steven B. Kanner, Chunjian Liu, Steven H. Spergel, John Wityak, Arthur M.P. Doweyko, Joseph A. Furch III

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Abstract

Novel thiazolyl compounds and salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds in the treatment of Tec family tyrosine kinase-associated disorders such as cancer, immunologic disorders and allergic disorders.

Claims22

Dependent claims

A compound of formula I

530
including diastereomers, enantiomers and salts thereof
where
Q1 is thiazolyl;
Q2 is aryl or heteroaryl optionally independently substituted with one or more substituents R1a;
Z is
(1) —O—,
(2) —S—,
(3) —NR4—,
(4) —CR4R5—,
(5) —CR4R5—O—CR4aR5a—,
(6) —CR4R5—NR4b—CR4aR5a—,
(7) —CR4R5—S—CR4aR5a—,
(8) —CR4R5—O—,
(9) —O—CR4R5—,
(10) —CR4R5—NR4b—,
(11) —NR4b—CR4R5—,
(12) —CR4R5—S—,
(13) —S—CR4R5—,
(14) —S(O)q where q is 1 or 2,
(15) —CR4R5—S(O)q—, or
(16) —S(O)q—CR4R5—;
R1 and R1a are independently
(1) hydrogen or R6,
(2) OH or —OR6,
(3) —SH or —SR6,
(4) —C(O)qH, —C(O)qR6, or —O—C(O)qR6,
(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, or
(12) —P(O)(OR6)2;
R2 and R3 are each independently H, -Z4-R6a, or -Z4-NR7aR8a
R4, R4a, R4b, R5 and R5a are each independently hydrogen, alkyl, aryl, aralkyl, cycloalkyl, or heteroarylalkyl;
R6, R6a, R6b and R6c are independently 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,
R7, R7a, R8, R8a, R9, R10, R11 and R12
(1) are each independently hydrogen, or -Z4R6b;
or
(2) R7 and R8, or R7a and R8a may together be alkylene, alkenylene, or heteroalkylene, 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 one or more groups Z3, or
(3) any two of R9, R10 and R11 may together be alkylene, alkenylene or heteroalkylene 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 one or more Z1, Z2 and Z3;
Z1, Z2 and Z3 are each independently
(1) hydrogen or Z6,
(2) —OH or -Z6,
(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) any two of Z1, Z2, and Z3 on a given substituent 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
(15) any two of Z1, Z2, and Z3 on a given substituent may together be —O—(CH2)q—O—;
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-,
(8) -Z11-C(O)-O-Z12-;
or
(9) alkyl
Z6 and Z6a are independently
(i) alkyl, hydroxyalkyl, alkoxyalkyl, 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 independently substituted by one or more of the groups (2) to (15) of the definition of Z1;
Z7, Z8, Z9 and Z10
(1) are each independently hydrogen or Z4Z6a;
(2) Z7 and Z8 may together be alkylene, alkenylene, or heteroalkylene 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 one or more Z1, Z2 and Z3, or
(3) Z7 or Z8, together with Z9, may be alkylene, alkenylene, or heteroalkylene 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 one or more Z1, Z2 and Z3;
Z11 and Z12 are each independently
(1) a single bond,
(2) alkylene,
(3) alkenylene, or
(4) alkynylene;
provided that said compound is other than
(a) a compound of formula X
531
where
Za is —CR4R5—, —NR4—, or —NR4—CR4R5—;
Q2 is as defined above;
Ra1 is alkyl, alkenyl, cylcoalkyl, heterocyclo, aryl, aralkyl or —NR7a1R8a1;
R7a1 is alkyl, cycloalkyl, heterocylco, aryl, —C(O)aryl, or aralkyl;
and
R8a1 is H, alkyl, alkenyl or alkynl;
or R7a1 and R7a1 combine to form a heterocylo group;
(b) a compound of formula XI
532
where
Zb is —CR4R5—, —NR4—, or —NR4—CR4R5—;
Q2b is aryl
Rb1 is H, alkyl optionally substituted with hydroxy, alkoxy, amino, alkylamino or dialkylamino;
L is phenyl or heteroaryl;
Rb2 is —NRb3Rb4, or —N(H)C(O)Rb5;
Rb3 and Rb4 are each independently H, cycloalkyl, alkyl or aryl;
or Rb3 and Rb4 together with the nitrogen atom to which they are attached combine to form 4-morpholinyl, 1-piperazinyl, N-alkyl-piperazinyl, N-aryl-piperazinyl, N-arylalkyl-piperazinyl, piperidinyl, pyrrolidinyl, 2-oxo-1-pyrrolidinyl, imidazolyl, or 3-azabicyclo[3.2.2]nonyl;
and
Rb5 is carboxy, alkyl, perfluoroalkyl, alkynyl, aryl, 2-oxo-pyrrolidinyl or piperidinyl;
(c) a compound of formula XIIa or XIIb
533
where
Q2 is as defined above;
Zc is CH2;
and
Rc1 is aryl or heterocyclo;
(d) a compound of formula XIII
534
where
Zd is CH2;
Q2d is aryl;
Rd1 is
—C(O)NRd7Rd8, (1) 535
where
c and d are zero to 1 providing c and d are not simultaneously zero;
e is zero to 5;
and
f is zero to 3;
or
536
where
c1, d1, f1, g1, k1, l1 and m1 are each independently zero or 1,
where c1, f1 and g1 are not simultaneously zero, and
where m1 is not zero when f1 or g1 is 1;
i1 is zero or 1, where k1 and l1 are zero when i1 is zero;
e1 is zero to 3
h1 is zero to 5;
j1 is zero to 2;
and
the sum of e1, h1 and j1 is 2 to 7;
A is —O—, —S—, —CH═CH—, or —N(Rd6)—;
Rd2 and Rd3 are independently H, alkyl, cycloalkyl or heteroaryl;
Rd4 is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl;
Rd5 is H, alkyl or cycloalkyl;
Rd6 is H, aryl, aralkyl, heteroaryl, hetercycloalkyl, carboxyalkyl, alkyl, cycloalkyl, —C(O)2alkyl, —C(O)2aralkyl, —C(O)alkyl, alkylsulphonyl, arylsulfonyl or heteroarylsulfonyl;
Rd7 and Rd8 together with the nitrogen atom to which they are attached combine to from a 5 to 8-membered saturated or unsaturated ring substituted with the group X;
and
X is
537
where
g is zero to 4;
i is zero or 1, with k being zero when i is zero;
the sum of h, i and j is ≧1 and ≦4;
k and m are independently zero or 1, with n being other than zero when m is 1;
and
the sum of 1, m and n is ≧2 and ≦5;
(e) a compound of formula XIV
538
where
Ze is —S—, —S(O)q— or —CH2—S(O)q—;
Q2e is
(2) aryl optionally substituted with one group selected from halo, hydroxy, alkoxy nitro, —NH2, -alkyl(NH2), —C(O)NH2, -alkylC(O)NH2 or -arylC(O)NH2;
or
(3) heteroaryl optionally substituted with one group selected from alkyl, hydroxy, haloalkyl or NH2;
Re1 is H, alkyl, hydroxyalkyl, halogen or carboxy;
and
Re2 is H, —C(O)alkyl, —SO2alkyl or —C(O)phenyl optionally substituted with halogen;
(f) a compound of formula XVa or XVb
539
where
Zf is —CR4R5—, —O—CR4R5, or —NR4—,;
Zf* is —CR4R5—;
Q2f is aryl or heteroaryl;
Rf1 is alkyl, aryl, heteroaryl, or cycloalkyl;
Rf1* is H, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heterocyclo, amino-substituted alkoxy, nitro, hydroxy, or NH2;
Rf2 is H, alkyl, aryl, heteroaryl, or cycloalkyl;
and
Rf3 is H, alkyl, cycloalkyl, aryl, halo, CF3, or heterocyclo;
(g) a compound of formula XVI
540
where
Zg is —NH— or —NH—CR4R5—;
Q2g is aryl, heteroaryl;
X is C or N
Q is a divalent radical containing 2 or 3 ring atoms each independently selected from C, N, O, S, CRg1, NRg1, which together with C* and N* form a 5 or 6-membered aromatic or nonaromatic ring;
Rg1 is hydroxy, halo, cyano, nitro, alkyl, alkenyl, cycloalkyl, non-aromatic heterocyclo, aryl, heteroaryl, or —C(O)Rg2;
or Rg1 cycloalkyl, heterocyclo or aryl that is fused to Q;
Rg2 is H, alkyl, cycloalkyl, non-aromatic heterocyclo, aryl, heteroaryl or —OC(O)Rg3;
Rg3 is H, alkyl, cycloalkyl, non-aromatic heterocyclo, aryl, heteroaryl or —C(O)NRg4Rg5;
Rg4 and Rg5 are independently H, alkyl, cycloalkyl, heterocyclo, aryl or —C(Rg6)═NRg7;
Rg6 is H, alkyl, cycloalkyl, heterocyclo, aryl, amino, alkylarnino, dialkylamino or —SO2Rg8;
Rg7 is H, alkyl, cycloalkyl, heterocyclo, aryl heteroaryl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, or —C(O)amino;
Rg8 is alkyl, cycloalkyl, heterocyclo, aryl or —SO2NRg9Rg10;
Rg9 and Rg10 are independently H, alkyl, cyclcoalkyl, heterocyclo, aryl, or —ORg11;
Rg11 is alkyl, cycloalkyl, heterocyclo, aryl, —C(O)Rg2, —OC(O)Rg3, —C(O)NRg4Rg5, —NRg12Rg13, or —SRg14;
Rg12 is H, alkyl, cycloalkyl, heterocyclo, aryl, hydroxy, alkoxy, amino, —C(O)Rg2, —OC(O)Rg3, —C(O)NRg4Rg5, or —C(Rg6)═NRg7;
Rg13 is H, alkyl, cycloalkyl, heterocyclo, aryl, —C(O)Rg2, —OC(O)Rg3, —C(O)NRg4Rg5, —C(Rg6)═NRg7, —SO2Rg8, or —SO2NRg9Rg10;
and
Rg14 is H, alkyl, cycloalkyl, heterocylco, aryl or —C(O)NRg4Rg5;
or
(h) a compound of formula XVII
541
where
Zh is —S— or —S(O)q—CR4R5—;
and
Q2h is heteroaryl

202 more elements

A compound of formula IIIa, IIIb or IIIc

543
including diastereomers, enantiomers and salts thereof
where
Z is
(1) —O—,
(2) —S—,
(3) —CR4R5—O—CR4aR5a—,
(4) —CR4R5—NR4b—CR4aR5a—,
(5) —CR4R5—S—CR4aR5a—,
(6) —CR4R5—O—,
(7) —CR4R5—NR4b—,
(8) —CR4R5—S—,
(9) —S—CR4R5—,
(10) —S(O)q—,
(11) —CR4R5—S(O)q—, or
(12) —S(O)q—CR4R5—;
R1, R1ab, R1ac and R1ad are independently
(1) hydrogen or R6,
(2) —OH or —OR6,
(3) —SH or —SR6,
(4) —C(O)qH, —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, or
(12) —P(O)(OR6)2;
R1aa is —C(O)qH, —C(O)qR6, -Z4-NR7R8, -Z4-N(R9)-Z5-NR10 R11 or -Z-N(R9)-Z5-R6;
R2 and R3 are each independently H, -Z4-R6a, or -Z4-NR7aR8a;
R4, R4a, R5 and R5a are each independently hydrogen, alkyl, aryl, aralkyl, cycloalkyl, or heteroarylalkyl;
R6, R6a, R6b and R6c are independently 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,
R7, R7a, R8, R8a, R9, R10, R11 and R12
(1) are each independently hydrogen, or -Z4R6b;
or
(2) R7 and R8, or R7a and R8a may together be alkylene, alkenylene, or heteroalkylene, 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 one or more groups Z3, or
(3) any two of R9, R10 and R11 may together be alkylene, alkenylene or heteroalkylene 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 one or more Z1, Z2 and Z3;
Z1, Z2 and Z3 are each independently
(1) hydrogen or Z6,
(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) any two of Z1, Z2, and Z3 on a given substituent 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
(15) any two of Z1, Z2, and Z3 on a given substituent may together be —O—(CH2)q—O—;
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-,
(8) -Z11-C(O)—O-Z12-;
or
(9) alkyl
Z6 and Z6a are independently
(i) alkyl, hydroxyalkyl, alkoxyalkyl, 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 independently substituted by one or more of the groups (2) to (15) of the definition of Z1;
Z7, Z8, Z9 and Z10
(1) are each independently hydrogen or -Z4-Z6a;
(2) Z7 and Z8 may together be alkylene, alkenylene, or heteroalkylene 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 one or more Z1, Z2 and Z3, or
(3) Z7 or Z8, together with Z9, may be alkylene, alkenylene, or heteroalkylene 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 one or more Z1, Z2 and Z3;
Z11 and Z12 are each independently
(1) a single bond,
(2) alkylene,
(3) alkenylene, or
(4) alkynylene;
provided said compound is other than a compound of formula XIV
544
where
Ze-S—, —S(O)q— or —CH2—S(O)q—;
Q2e is phenyl optionally substituted with one group selected from halo, hydroxy, alkoxy nitro, —NH2, -alkyl(NH2), —C(O)NH2, -alkylC(O)NH2 or -arylC(O)NH2;
Re1 is H, alkyl, hydroxyalkyl, halogen or carboxy;
and
Re2 is H, —C(O)alkyl, —SO2alkyl or —C(O)phenyl optionally substituted with halogen.

85 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/642,040Filed 15 Aug 2003
Priority: 21 Dec 2000
Published: 10 Jun 2004
Term ends: Not estimatedThe source records don’t support an estimate.

Classification22 codes

C07D 417/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
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 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 11/00
Drugs for disorders of the respiratory system

Family

Application60/257,830Us provisional application · filed 21 Dec 2000
Application10/027,982Division · filed 20 Dec 2001
Application10/642,040Division · filed 15 Aug 2003
US 2003/0069238 A1Published application
US 6,706,717 B2Related patent
US 6,953,795 B2Related patent
US 2004/0110752 A1This patent

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

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Abstract

A compound of formula I

530
including diastereomers, enantiomers and salts thereof
where
Q1 is thiazolyl;
Q2 is aryl or heteroaryl optionally independently substituted with one or more substituents R1a;
Z is
(1) —O—,
(2) —S—,
(3) —NR4—,
(4) —CR4R5—,
(5) —CR4R5—O—CR4aR5a—,
(6) —CR4R5—NR4b—CR4aR5a—,
(7) —CR4R5—S—CR4aR5a—,
(8) —CR4R5—O—,
(9) —O—CR4R5—,
(10) —CR4R5—NR4b—,
(11) —NR4b—CR4R5—,
(12) —CR4R5—S—,
(13) —S—CR4R5—,
(14) —S(O)q where q is 1 or 2,
(15) —CR4R5—S(O)q—, or
(16) —S(O)q—CR4R5—;
R1 and R1a are independently
(1) hydrogen or R6,
(2) OH or —OR6,
(3) —SH or —SR6,
(4) —C(O)qH, —C(O)qR6, or —O—C(O)qR6,
(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, or
(12) —P(O)(OR6)2;
R2 and R3 are each independently H, -Z4-R6a, or -Z4-NR7aR8a
R4, R4a, R4b, R5 and R5a are each independently hydrogen, alkyl, aryl, aralkyl, cycloalkyl, or heteroarylalkyl;
R6, R6a, R6b and R6c are independently 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,
R7, R7a, R8, R8a, R9, R10, R11 and R12
(1) are each independently hydrogen, or -Z4R6b;
or
(2) R7 and R8, or R7a and R8a may together be alkylene, alkenylene, or heteroalkylene, 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 one or more groups Z3, or
(3) any two of R9, R10 and R11 may together be alkylene, alkenylene or heteroalkylene 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 one or more Z1, Z2 and Z3;
Z1, Z2 and Z3 are each independently
(1) hydrogen or Z6,
(2) —OH or -Z6,
(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) any two of Z1, Z2, and Z3 on a given substituent 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
(15) any two of Z1, Z2, and Z3 on a given substituent may together be —O—(CH2)q—O—;
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-,
(8) -Z11-C(O)-O-Z12-;
or
(9) alkyl
Z6 and Z6a are independently
(i) alkyl, hydroxyalkyl, alkoxyalkyl, 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 independently substituted by one or more of the groups (2) to (15) of the definition of Z1;
Z7, Z8, Z9 and Z10
(1) are each independently hydrogen or Z4Z6a;
(2) Z7 and Z8 may together be alkylene, alkenylene, or heteroalkylene 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 one or more Z1, Z2 and Z3, or
(3) Z7 or Z8, together with Z9, may be alkylene, alkenylene, or heteroalkylene 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 one or more Z1, Z2 and Z3;
Z11 and Z12 are each independently
(1) a single bond,
(2) alkylene,
(3) alkenylene, or
(4) alkynylene;
provided that said compound is other than
(a) a compound of formula X
531
where
Za is —CR4R5—, —NR4—, or —NR4—CR4R5—;
Q2 is as defined above;
Ra1 is alkyl, alkenyl, cylcoalkyl, heterocyclo, aryl, aralkyl or —NR7a1R8a1;
R7a1 is alkyl, cycloalkyl, heterocylco, aryl, —C(O)aryl, or aralkyl;
and
R8a1 is H, alkyl, alkenyl or alkynl;
or R7a1 and R7a1 combine to form a heterocylo group;
(b) a compound of formula XI
532
where
Zb is —CR4R5—, —NR4—, or —NR4—CR4R5—;
Q2b is aryl
Rb1 is H, alkyl optionally substituted with hydroxy, alkoxy, amino, alkylamino or dialkylamino;
L is phenyl or heteroaryl;
Rb2 is —NRb3Rb4, or —N(H)C(O)Rb5;
Rb3 and Rb4 are each independently H, cycloalkyl, alkyl or aryl;
or Rb3 and Rb4 together with the nitrogen atom to which they are attached combine to form 4-morpholinyl, 1-piperazinyl, N-alkyl-piperazinyl, N-aryl-piperazinyl, N-arylalkyl-piperazinyl, piperidinyl, pyrrolidinyl, 2-oxo-1-pyrrolidinyl, imidazolyl, or 3-azabicyclo[3.2.2]nonyl;
and
Rb5 is carboxy, alkyl, perfluoroalkyl, alkynyl, aryl, 2-oxo-pyrrolidinyl or piperidinyl;
(c) a compound of formula XIIa or XIIb
533
where
Q2 is as defined above;
Zc is CH2;
and
Rc1 is aryl or heterocyclo;
(d) a compound of formula XIII
534
where
Zd is CH2;
Q2d is aryl;
Rd1 is
—C(O)NRd7Rd8, (1) 535
where
c and d are zero to 1 providing c and d are not simultaneously zero;
e is zero to 5;
and
f is zero to 3;
or
536
where
c1, d1, f1, g1, k1, l1 and m1 are each independently zero or 1,
where c1, f1 and g1 are not simultaneously zero, and
where m1 is not zero when f1 or g1 is 1;
i1 is zero or 1, where k1 and l1 are zero when i1 is zero;
e1 is zero to 3
h1 is zero to 5;
j1 is zero to 2;
and
the sum of e1, h1 and j1 is 2 to 7;
A is —O—, —S—, —CH═CH—, or —N(Rd6)—;
Rd2 and Rd3 are independently H, alkyl, cycloalkyl or heteroaryl;
Rd4 is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl;
Rd5 is H, alkyl or cycloalkyl;
Rd6 is H, aryl, aralkyl, heteroaryl, hetercycloalkyl, carboxyalkyl, alkyl, cycloalkyl, —C(O)2alkyl, —C(O)2aralkyl, —C(O)alkyl, alkylsulphonyl, arylsulfonyl or heteroarylsulfonyl;
Rd7 and Rd8 together with the nitrogen atom to which they are attached combine to from a 5 to 8-membered saturated or unsaturated ring substituted with the group X;
and
X is
537
where
g is zero to 4;
i is zero or 1, with k being zero when i is zero;
the sum of h, i and j is ≧1 and ≦4;
k and m are independently zero or 1, with n being other than zero when m is 1;
and
the sum of 1, m and n is ≧2 and ≦5;
(e) a compound of formula XIV
538
where
Ze is —S—, —S(O)q— or —CH2—S(O)q—;
Q2e is
(2) aryl optionally substituted with one group selected from halo, hydroxy, alkoxy nitro, —NH2, -alkyl(NH2), —C(O)NH2, -alkylC(O)NH2 or -arylC(O)NH2;
or
(3) heteroaryl optionally substituted with one group selected from alkyl, hydroxy, haloalkyl or NH2;
Re1 is H, alkyl, hydroxyalkyl, halogen or carboxy;
and
Re2 is H, —C(O)alkyl, —SO2alkyl or —C(O)phenyl optionally substituted with halogen;
(f) a compound of formula XVa or XVb
539
where
Zf is —CR4R5—, —O—CR4R5, or —NR4—,;
Zf* is —CR4R5—;
Q2f is aryl or heteroaryl;
Rf1 is alkyl, aryl, heteroaryl, or cycloalkyl;
Rf1* is H, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heterocyclo, amino-substituted alkoxy, nitro, hydroxy, or NH2;
Rf2 is H, alkyl, aryl, heteroaryl, or cycloalkyl;
and
Rf3 is H, alkyl, cycloalkyl, aryl, halo, CF3, or heterocyclo;
(g) a compound of formula XVI
540
where
Zg is —NH— or —NH—CR4R5—;
Q2g is aryl, heteroaryl;
X is C or N
Q is a divalent radical containing 2 or 3 ring atoms each independently selected from C, N, O, S, CRg1, NRg1, which together with C* and N* form a 5 or 6-membered aromatic or nonaromatic ring;
Rg1 is hydroxy, halo, cyano, nitro, alkyl, alkenyl, cycloalkyl, non-aromatic heterocyclo, aryl, heteroaryl, or —C(O)Rg2;
or Rg1 cycloalkyl, heterocyclo or aryl that is fused to Q;
Rg2 is H, alkyl, cycloalkyl, non-aromatic heterocyclo, aryl, heteroaryl or —OC(O)Rg3;
Rg3 is H, alkyl, cycloalkyl, non-aromatic heterocyclo, aryl, heteroaryl or —C(O)NRg4Rg5;
Rg4 and Rg5 are independently H, alkyl, cycloalkyl, heterocyclo, aryl or —C(Rg6)═NRg7;
Rg6 is H, alkyl, cycloalkyl, heterocyclo, aryl, amino, alkylarnino, dialkylamino or —SO2Rg8;
Rg7 is H, alkyl, cycloalkyl, heterocyclo, aryl heteroaryl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, or —C(O)amino;
Rg8 is alkyl, cycloalkyl, heterocyclo, aryl or —SO2NRg9Rg10;
Rg9 and Rg10 are independently H, alkyl, cyclcoalkyl, heterocyclo, aryl, or —ORg11;
Rg11 is alkyl, cycloalkyl, heterocyclo, aryl, —C(O)Rg2, —OC(O)Rg3, —C(O)NRg4Rg5, —NRg12Rg13, or —SRg14;
Rg12 is H, alkyl, cycloalkyl, heterocyclo, aryl, hydroxy, alkoxy, amino, —C(O)Rg2, —OC(O)Rg3, —C(O)NRg4Rg5, or —C(Rg6)═NRg7;
Rg13 is H, alkyl, cycloalkyl, heterocyclo, aryl, —C(O)Rg2, —OC(O)Rg3, —C(O)NRg4Rg5, —C(Rg6)═NRg7, —SO2Rg8, or —SO2NRg9Rg10;
and
Rg14 is H, alkyl, cycloalkyl, heterocylco, aryl or —C(O)NRg4Rg5;
or
(h) a compound of formula XVII
541
where
Zh is —S— or —S(O)q—CR4R5—;
and
Q2h is heteroaryl

202 more elements

Facts

Application

10/642,040Filed 15 Aug 2003

Priority

21 Dec 2000

Published

10 Jun 2004

Term ends

Not estimatedThe source records don’t support an estimate.

Classification22 codes

C07D 417/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
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 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 11/00
Drugs for disorders of the respiratory system

Family

Application60/257,830Us provisional application · filed 21 Dec 2000

Application10/027,982Division · filed 20 Dec 2001

Application10/642,040Division · filed 15 Aug 2003

US 2003/0069238 A1Published application

US 6,706,717 B2Related patent

US 6,953,795 B2Related patent

US 2004/0110752 A1This patent

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