CA2474192A1 - Nicotinamide derivates useful as p38 inhibitors - Google Patents

Nicotinamide derivates useful as p38 inhibitors Download PDF

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CA2474192A1
CA2474192A1 CA002474192A CA2474192A CA2474192A1 CA 2474192 A1 CA2474192 A1 CA 2474192A1 CA 002474192 A CA002474192 A CA 002474192A CA 2474192 A CA2474192 A CA 2474192A CA 2474192 A1 CA2474192 A1 CA 2474192A1
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optionally substituted
6alkyl
groups
compound
halogen
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CA2474192C (en
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Nicola Mary Aston
Paul Bamborough
Ann Louise Walker
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GlaxoSmithKline LLC
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Abstract

Compounds of formula (I), are inhibitors of p38 kinase and are useful in the treatment of conditions or disease states mediated by p38 kinase activity or mediated by cytokines produced by the activity of p38.

Claims (13)

1. A compound of formula (I):

wherein R1 is selected from hydrogen, C1-6alkyl optionally substituted by up to three groups selected from C1-6alkoxy, halogen and hydroxy, C2-6alkenyl, C3-7cycloalkyl optionally substituted by one or more C1-6alkyl groups, phenyl optionally substituted by up to three groups selected from R5 and R6, and heteroaryl optionally substituted by up to three groups selected from R5 and R6, R2 is selected from hydrogen, C1-6alkyl and-(CH2)q-C3-7cycloalkyl optionally substituted by one or more C1-6alkyl groups, or (CH2)m R1 and R2, together with the nitrogen atom to which they are bound, form a four- to six-membered heterocyclic ring optionally substituted by up to three C1-6alkyl groups;
R3 is chloro or methyl;
R4 is the group -NH-CO-R7 or -CO-NH-(CH2)q-R8;
R5 is selected from C1-6alkyl, C1-6alkoxy, -(CH2)q-C3-7cycloalkyl optionally substituted by one or more C1-6alkyl groups, -CONR9R10, -NHCOR10, -SO2NHR9, -(CH2) S NHSO2R10, halogen, CN, OH, -(CH2)S NR11R12, and trifluoromethyl;
R6 is selected from C1-6alkyl, C1-6alkoxy, halogen, trifluoromethyl and-(CH2)S NR11R12;
R7 is selected from hydrogen, C1-6alkyl, -(CH2)q-C3-7cycloalkyl optionally substituted by one or more C1-6alkyl groups, trifluoromethyl, -(CH2)r heteroaryl optionally substituted by R13 and/or R14, and -(CH2)r phenyl optionally substituted by R13 and/or R14;
R8 is selected from hydrogen, C1-6alkyl, C3-7cycloalkyl optionally substituted by one or more C1-6alkyl groups, CONHR9, phenyl optionally substituted by R13 and/or R14, and heteroaryl optionally substituted by R13 and/or R14;

R9 and R10 are each independently selected from hydrogen and C1-6alkyl, or R9 and R10, together with the nitrogen atom to which they are bound, form a five- to six-membered heterocyclic ring optionally containing one additional heteroatom selected from oxygen, sulfur and N-R15, wherein the ring may be substituted by up to two C1-6alkyl groups;
R11 is selected from hydrogen, C1-6alkyl and-(CH2)q-C3-7cycloalkyl optionally substituted by one or more C1-6alkyl groups, R12 is selected from hydrogen and C1-6alkyl, or R11 and R12, together with the nitrogen atom to which they are bound, form a five or six-membered heterocyclic ring optionally containing one additional heteroatom selected from oxygen, sulfur and N-R15;
R13 is selected from C1-6alkyl, C1-6alkoxy,-(CH2)q-C3-7cycloalkyl optionally substituted by one or more C1-6alkyl groups, -CONR9R10, -NHCOR10, halogen, CN, -(CH2)s NR11R12, trifluoromethyl, phenyl optionally substituted by one or more R14 groups and heteroaryl optionally substituted by one or more R14 groups;
R14 is selected from C1-6alkyl, C1-6alkoxy, halogen, trifluoromethyl and -NR11R12;
R15 is selected from hydrogen and methyl;
X and Y are each independently selected from hydrogen, methyl and halogen;
Z is halogen;
m is selected from 0, 1, 2, 3 and 4, wherein each carbon atom of the resulting carbon chain may be optionally substituted with up to two groups selected independently from C1-6alkyl and halogen;
n is selected from 0, 1 and 2;
q is selected from 0, 1 and 2;
r is selected from 0 and 1; and s is selected from 0, 1, 2 and 3.
2. A compound according to claim 1 wherein R1 is selected from C1-6alkyl, C2-6alkenyl, C3-7cycloalkyl optionally substituted by one or more C1-6alkyl groups, phenyl optionally substituted by up to three substituents selected from R5 and R6, heteroaryl optionally substituted by up to three substituents selected from R5 and R6.
3. A compound according to claim 1 or claim 2 wherein R2 is hydrogen.
4. A compound according to any one of the preceding claims wherein R3 is methyl.
5. A compound according to any one of the preceding claims wherein X is fluorine.
6. A compound according to any one of the preceding claims wherein R7 is selected from C1-6alkyl, -(CH2)q-C3-7cycloalkyl, trifluoromethyl, -(CH2)r heteroaryl optionally substituted by R13 and/or R14, and -(CH2)r phenyl optionally substituted by C1-6alkyl, C1-6alkoxy, -(CH2)q-C3-7cycloalkyl, -CONR9R10, -NHCOR10, halogen, CN, trifluoromethyl, phenyl optionally substituted by one or more R14 groups and/or heteroaryl optionally substituted by one or more R14 groups.
7. A compound according to any one of the preceding claims wherein R8 is selected from C3-7cycloalkyl, CONHR9, heteroaryl optionally substituted by R13 and/or R14, and phenyl optionally substituted by C1-6alkyl, C1-6alkoxy, -(CH2)q-C3-7cycloalkyl, -CONR9R10, -NHCOR10, halogen, CN, trifluoromethyl, phenyl optionally substituted by one or more R14 groups and/or heteroaryl optionally substituted by one or more R14 groups.
8. A compound according to claim 1 as defined in any one of Examples 1 to 123.
9. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 8 in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients.
10. A method for treating a condition or disease state mediated by p38 kinase activity or mediated by cytokines produced by the activity of p38 kinase comprising administering to a patient in need thereof a compound as claimed in any one of claims 1 to 8.
11. A compound as claimed in any one of claims 1 to 8 for use in therapy.
12. Use of a compound as claimed in any one of claims 1 to 8 in the manufacture of a medicament for use in the treatment of a condition or disease state mediated by p38 kinase activity or mediated by cytokines produced by the activity of p38 kinase.
13. A process for preparing a compound of formula (I) as claimed in any one of claims 1 to 8 which comprises (a) reacting a compound of (II) in which R1, R2, Z, m and n are as defined in claim 1 and W is halogen, with a compound of formula (III) in which R3, R4, X and Y are as defined in claim 1, in the presence of a catalyst, or (b) reacting a compound of formula (VIII) with a compound of formula (III) as hereinbefore defined and then reacting the acid thus formed with an amine of formula (V) in which R1, R2 and m are as defined in claim 1, under amide forming conditions, or (c) reacting a compound of formula (II) as hereinbefore defined with a compound of formula (IX) in which R3, R4, X and Y are as defined in claim 1, in the presence of a catalyst.
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