US 7,071,333 B2Granted

Triazolopurine-based tricyclic compounds and pharmaceutical compositions comprising same

AssigneeBristol-Myers Squibb Company

InventorsDonald Combs, Charles M. Langevine, Yuping Qiu, Fred Christopher Zusi

Life of this patent

Estimating the term…

Abstract

The present invention provides for triazolopurine-based tricyclic compounds having the formula (I), wherein R1, R2, R3, R4, and R5 are as described herein. The present invention further provides pharmaceutical compositions comprising such compounds, as well as the use of such compounds for treating inflammatory and immune diseases.

Claims10

Dependent claims

A compound of Formula (I),

enantiomers, diastereomers, and salts, thereof wherein
R1 is
(a) hydrogen, or
(b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z1, Z2 and Z3;
(c) —OR9a;
R2 is
(a) hydrogen, halo, cyano,
(b) alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, heterocyclooxy, aryloxy, heteroaryloxy, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z1a, Z2a and Z3a;
or
(c) —OR9a, —SR9a or —SO2R9a
R3 and R4 are independently
(a) hydrogen,
(b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z1b, Z2b and Z3b;
(c) —OR10, —NR11R12, —N(R11)C(O)R10, —N(R11)C(O)OR10, —N(R11)SO2R13, or —C(O)NR11R12, —SO2NR11R12, —N(R11)C(O)NR11aR12, or —N(R11)SO2NR11aR12;
or
(d) R3 and R4 together with the nitrogen atom to which they are attached combine to form a heterocyclo ring optionally independently substituted as valence allows with one or more Z1b, Z2b and Z3b;
R5 is
(a) hydrogen, hydroxy, halo, or cyano,
(b) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z1d, Z2d and Z3d;
or
(c) —OR6a, —SR9a, SO2R9a, SO2NR7aR8a, —NR7aR8a, —N(R7a)SO2R9, —N(R7a)SO2NR7bR8b, —N(R7a)C(O)R6a, —N(R7a)C(O)NR7bR8b, —N(R7a)C(O)OR6a, —C(O)R6a, —C(O)OR6a, —OC(O)R6a, —C(O)NR7aR8a, or —OC(O)NR7aR8a;
R6a and R6b are independently
(a) hydrogen, or
(b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z1c, Z2c and Z3c;
R7a, R7b, R8a and R8b are independently
(a) hydrogen,
(b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z1d, Z2d and Z3d;
or
(c) —OR6b, —NR7cR8c, —N(R7c)SO2R9b, —N(R7c)C(O)R6b, —N(R7c)C(O)OR6b, —SO2NR7cR8c, —SO2R9b, —C(O)R6b, —C(O)OR6b, or —C(O)NR7cR8c;
(d) R7a and R8a together with the nitrogen atom to which they are attached combine to form a heterocyclo ring optionally independently substituted as valence allows with one or more Z1d, Z2d and Z3d;
R7c and R8c are independently
(a) hydrogen,
(b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z1d, Z2d and Z3d;
(c) R7c and R8c together with the nitrogen atom to which they are attached combine to form a heterocyclo ring optionally independently substituted as valence allows with one or more Z1d, Z2d and Z3d;
R9, R9a and R9b are independently alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z1d, Z2d and Z3d;
R10, R11, R11a and R12 are independently
(a) hydrogen, or
(b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z1e, Z2e and Z3e;
(c) R11 and R12 together with the nitrogen atom to which they are attached combine to form a heterocyclo ring optionally independently substituted as valence allows with one or more Z1d, Z2d and Z3d;
R13 is alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z1e, Z2e and Z3e;
Z1-1e, Z2-2e, and Z3-3e are optional substituents at each occurrence independently selected from W1-5 optionally substituted as valance allows with V1-5;
where W1-5 are independently
(1) a bond
(2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl )alkyl, cycloalkenyl, (cycloalkenyl )alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl;
or
where V1-5 are independently
(1) H
(2) alkyl, haloalkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl;
(3) —U1—O—Y5,
(4) —U1—S—Y5,
(5) —U1—C(O)tH, —U1—C(O)t—Y5 where t is 1 or 2,
(6) —U1—SO3—H, or —U1—S(O)tY5,
(7) —U1-halo,
(8) —U1-cyano,
(9) —U1-nitro,
(10) —U1—NY2Y3,
(11) —U1—N(Y4)—C(O)—Y1,
(12) —U1—N(Y4)—C(S)—Y1,
(13) —U1—N(Y4)—C(O)—NY2Y3,
(14) —U1—N(Y4)—C(S)—NY2Y3,
(15) —U1—N(Y4)—C(O)O—Y5,
(16) —U1—N(Y4)—S(O)2—Y1,
(17) —U1—N(Y4)—S(O)2—NY2Y3,
(18) —U1—C(O)—NY2Y3,
(19) —U1—OC(O)—NY2Y3,
(20) —U1—S(O)2—N(Y4)—Y1,
(21) —U1—N(Y4)—C(═NV1a)—NY2Y3,
(22) —U1—N(Y4)—C(═NV1a)—Y1,
(23) —U1—C(═NV1a)—NY2Y3,
(24) oxo;
(25) —Y5;
(26) —U1—C(O)—NY2—OY5,
V1a is independently hydrogen, alkyl, —CN, —C(O)Y1, —S(O)2Y5, S(O)2NY2Y3;
Y1, Y2, Y3, Y4 and Y5
(1) are each independently hydrogen, alkyl, haloalkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl;
or
(2) Y2 and Y3 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
(3) Y2 or Y3, together with Y1, 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, or
(4) Y2 and Y3 together with the nitrogen atom to which they are attached may combine to form a group —N═CY6Y7 where Y6 and Y7 are each independently H or alkyl;
and
U1 is independently
(1) a single bond,
(2) alkylene,
(3) alkenylene,
(4) alkynylene,
(5) —U2—O—U3—,
(6) —U2—NY4—U3—,
(7) —U2—S—U3—, or
(8) —U2—S(O)2—U3—,
U2 is independently selected from
(1) a single bond,
(2) alkylene,
(3) alkenylene,
(4) alkynylene;
and
U3 is independently selected from
(1) alkylene,
(2) alkenylene,
(3) alkynylene.

96 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/901,677Filed 29 Jul 2004 · us provisional application
Priority: 30 Jul 2003
Published: US 2005/0038054 A117 Feb 2005
Granted: 4 Jul 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07D 487/14
In which the condensed system contains three hetero rings: ortho-condensed systems
A61P 11/06
Drugs for disorders of the respiratory system: antiasthmatics
A61P 19/02
Drugs for skeletal disorders: for joint disorders, e.g. arthritis, arthrosis
C07D
Heterocyclic compounds

Family

Application60/491,170Us provisional application · filed 30 Jul 2003
US 2005/0038054 A1Pre-grant publication · published 17 Feb 2005
US 7,071,333 B2This patent

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

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Abstract

A compound of Formula (I),

enantiomers, diastereomers, and salts, thereof wherein
R1 is
(a) hydrogen, or
(b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z1, Z2 and Z3;
(c) —OR9a;
R2 is
(a) hydrogen, halo, cyano,
(b) alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, heterocyclooxy, aryloxy, heteroaryloxy, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z1a, Z2a and Z3a;
or
(c) —OR9a, —SR9a or —SO2R9a
R3 and R4 are independently
(a) hydrogen,
(b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z1b, Z2b and Z3b;
(c) —OR10, —NR11R12, —N(R11)C(O)R10, —N(R11)C(O)OR10, —N(R11)SO2R13, or —C(O)NR11R12, —SO2NR11R12, —N(R11)C(O)NR11aR12, or —N(R11)SO2NR11aR12;
or
(d) R3 and R4 together with the nitrogen atom to which they are attached combine to form a heterocyclo ring optionally independently substituted as valence allows with one or more Z1b, Z2b and Z3b;
R5 is
(a) hydrogen, hydroxy, halo, or cyano,
(b) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z1d, Z2d and Z3d;
or
(c) —OR6a, —SR9a, SO2R9a, SO2NR7aR8a, —NR7aR8a, —N(R7a)SO2R9, —N(R7a)SO2NR7bR8b, —N(R7a)C(O)R6a, —N(R7a)C(O)NR7bR8b, —N(R7a)C(O)OR6a, —C(O)R6a, —C(O)OR6a, —OC(O)R6a, —C(O)NR7aR8a, or —OC(O)NR7aR8a;
R6a and R6b are independently
(a) hydrogen, or
(b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z1c, Z2c and Z3c;
R7a, R7b, R8a and R8b are independently
(a) hydrogen,
(b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z1d, Z2d and Z3d;
or
(c) —OR6b, —NR7cR8c, —N(R7c)SO2R9b, —N(R7c)C(O)R6b, —N(R7c)C(O)OR6b, —SO2NR7cR8c, —SO2R9b, —C(O)R6b, —C(O)OR6b, or —C(O)NR7cR8c;
(d) R7a and R8a together with the nitrogen atom to which they are attached combine to form a heterocyclo ring optionally independently substituted as valence allows with one or more Z1d, Z2d and Z3d;
R7c and R8c are independently
(a) hydrogen,
(b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z1d, Z2d and Z3d;
(c) R7c and R8c together with the nitrogen atom to which they are attached combine to form a heterocyclo ring optionally independently substituted as valence allows with one or more Z1d, Z2d and Z3d;
R9, R9a and R9b are independently alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z1d, Z2d and Z3d;
R10, R11, R11a and R12 are independently
(a) hydrogen, or
(b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z1e, Z2e and Z3e;
(c) R11 and R12 together with the nitrogen atom to which they are attached combine to form a heterocyclo ring optionally independently substituted as valence allows with one or more Z1d, Z2d and Z3d;
R13 is alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may be optionally independently substituted as valence allows with one or more Z1e, Z2e and Z3e;
Z1-1e, Z2-2e, and Z3-3e are optional substituents at each occurrence independently selected from W1-5 optionally substituted as valance allows with V1-5;
where W1-5 are independently
(1) a bond
(2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl )alkyl, cycloalkenyl, (cycloalkenyl )alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl;
or
where V1-5 are independently
(1) H
(2) alkyl, haloalkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl;
(3) —U1—O—Y5,
(4) —U1—S—Y5,
(5) —U1—C(O)tH, —U1—C(O)t—Y5 where t is 1 or 2,
(6) —U1—SO3—H, or —U1—S(O)tY5,
(7) —U1-halo,
(8) —U1-cyano,
(9) —U1-nitro,
(10) —U1—NY2Y3,
(11) —U1—N(Y4)—C(O)—Y1,
(12) —U1—N(Y4)—C(S)—Y1,
(13) —U1—N(Y4)—C(O)—NY2Y3,
(14) —U1—N(Y4)—C(S)—NY2Y3,
(15) —U1—N(Y4)—C(O)O—Y5,
(16) —U1—N(Y4)—S(O)2—Y1,
(17) —U1—N(Y4)—S(O)2—NY2Y3,
(18) —U1—C(O)—NY2Y3,
(19) —U1—OC(O)—NY2Y3,
(20) —U1—S(O)2—N(Y4)—Y1,
(21) —U1—N(Y4)—C(═NV1a)—NY2Y3,
(22) —U1—N(Y4)—C(═NV1a)—Y1,
(23) —U1—C(═NV1a)—NY2Y3,
(24) oxo;
(25) —Y5;
(26) —U1—C(O)—NY2—OY5,
V1a is independently hydrogen, alkyl, —CN, —C(O)Y1, —S(O)2Y5, S(O)2NY2Y3;
Y1, Y2, Y3, Y4 and Y5
(1) are each independently hydrogen, alkyl, haloalkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl;
or
(2) Y2 and Y3 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
(3) Y2 or Y3, together with Y1, 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, or
(4) Y2 and Y3 together with the nitrogen atom to which they are attached may combine to form a group —N═CY6Y7 where Y6 and Y7 are each independently H or alkyl;
and
U1 is independently
(1) a single bond,
(2) alkylene,
(3) alkenylene,
(4) alkynylene,
(5) —U2—O—U3—,
(6) —U2—NY4—U3—,
(7) —U2—S—U3—, or
(8) —U2—S(O)2—U3—,
U2 is independently selected from
(1) a single bond,
(2) alkylene,
(3) alkenylene,
(4) alkynylene;
and
U3 is independently selected from
(1) alkylene,
(2) alkenylene,
(3) alkynylene.

96 more elements

Facts

Application

10/901,677Filed 29 Jul 2004 · us provisional application

Priority

30 Jul 2003

Published

US 2005/0038054 A117 Feb 2005

Granted

4 Jul 2006

Term ends

Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07D 487/14
In which the condensed system contains three hetero rings: ortho-condensed systems
A61P 11/06
Drugs for disorders of the respiratory system: antiasthmatics
A61P 19/02
Drugs for skeletal disorders: for joint disorders, e.g. arthritis, arthrosis
C07D
Heterocyclic compounds