US 2011/0086834 A1 · ALKYNYL ALCOHOLS AS KINASE INHIBITORS

Abstract

Selected compounds are effective for prophylaxis and treatment of inflammation and inflammatory disorders, such as NIK-mediated disorders. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, inflammation and the like.

A compound of formula I

enantiomers, diastereomers and salts thereof wherein
R1 is selected from
any of which may be optionally substituted with one or more Rx groups as allowed by valance;
provided that when R1 is
where U is CH and R6 is H, then R5
is other than
R2 is alkyl or haloalkyl;
R3 is alkyl, cycloalkyl, haloalkyl, —C(═O)R7, —C(═O)OR7, —C(═O)NR8R9, aryl or heteroaryl wherein either of said aryl or heteroaryl may be optionally substituted with one or more Rx as allowed by valance;
or R2 and R3 together with the carbon atom to which they are attached may combine to form
which may be optionally substituted with one or more Rx groups as allowed by valance;
R4 and R4* are independently
i) pyridyl, pyrimidyl, pyrazinyl, triazinyl, purinyl, pyrrolopyrimidyl, triazolopyrimidyl, furopyrimidyl, thienopyrimidyl, oxazolopyrimidyl, or thiazolopyrimidyl, each of which is substituted with at least one R10 group, and any of which may be optionally substituted with one or more Rx groups as allowed by valance;
or
ii) oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, or —C(═O)R7* any of which may be optionally substituted with one or more Rx groups as allowed by valance;
provided R4 is other than —C(═O)R7* when R1 is
where U is CH and R6 is H, and R5 is either —(CH2)k—N(R8)(R4) or —(CH2)k—R4;
R5 is —(CH2)k—R4, —(CH2)k—N(R8)(R4), —(CH2)k—OR4, —(CH2)k—C(═O)R4;
—(CH2)k—C(═O)OR4, —(CH2)k—C(═O)N(R8)(R4) or —(CH2)k—NR8—(C═O)R4;
R6 is H, halo, alkyl, —(CH2)k—OR11, —(CH2)k—N(R12)(R13), —(CH2)k—C(═O)R11, —(CH2)k—C(═O)OR11;
R7, R7* and R7+are each independently
(i) H, or
(ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, alkoxyalkyl, hydroxyalkyl or NR8R9-alkyl any of which may be optionally substituted with one or more Rx groups as allowed by valance;
R8, R9, R8+and R9+ are each independently
(i) H;
(ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalky, alkoxyalkyl, hydroxyalkyl or (NR12R13)-alkyl, any of which may be optionally substituted with one or more Rx groups as allowed by valance;
(iii) or R8 and R9 together with the nitrogen atom to which they are attached may combine to form a heterocyclyl ring optionally substituted with one or more Rx groups as allowed by valance;
(iv) or R8+ and R9+ together with the nitrogen atom to which they are attached may combine to form a heterocyclyl ring optionally substituted with one or more Rx groups as allowed by valance;
R10 is H, —NR14R15, or —C(═O)NR14R15;
R11 is
(i) H, or
(ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl any of which may be optionally substituted with one or more Rx groups as allowed by valance;
R12 and R13 are each independently
(i) H;
(ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, alkoxyalkyl, hydroxyalkyl or (NR8R9)-alkyl, any of which may be optionally substituted with one or more Rx groups as allowed by valance;
(iii) or R12 and R13 together with the nitrogen atom to which they are attached may combine to form a heterocyclyl ring optionally substituted with one or more Rx groups as allowed by valance;
R14 and R15 are each independently
(i) H;
(ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, alkoxyalkyl, hydroxyalkyl or (NR12R13)-alkyl, any of which may be optionally substituted with one or more Rx groups as allowed by valance;
(iii) or R14 and R15 together with the nitrogen atom to which they are attached may combine to form a heterocyclyl ring optionally substituted with one or more Rx groups as allowed by valance;
Ra, Rb, Rc Rd and R* are each independently H or Rx
or Ra and Rb together with the carbon atom to which they are attached may combine to form a carbonyl group;
or Rb together with either Rc or R* may combine to form a bond;
or Ra and Re, together with the atoms to which they are respectively attached, may combine to form
which may be optionally substituted with one or more Rx groups as allowed by valance;
or Ra and R4*, together with the atoms to which they are respectively attached, may combine to form
which may be optionally substituted with one or more Rx groups as allowed by valance;
or Rc and Rd together with the carbon atom to which they are each attached may combine to form
which may be optionally substituted with one or more Rx groups as allowed by valance;
Re is H, R4, or Rx;
Rx is an optional substituent independently selected at each occurrence from halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene)q-OR7+, -(alkylene)q-S(O)nR7+, -(alkylene)q-NR8+R9+, -(alkylene)q-C(═O)R7+, -(alkylene)q-C(═S)R7+, -(alkylene)q-C(═O)OR7+, -(alkylene)q-OC(═O)R7+, -(alkylene)q-C(═S)OR7+, -(alkylene)q-C(═O)NR8+R9+, -(alkylene)q-C(═S)NR8+R9+, -(alkylene)q-N(R15)C(═O)NR8+R9+, -(alkylene)q-N(R15)C(═S)NR8+R9+, -(alkylene)q-N(R15)C(═O)R7+, -(alkylene)q-N(R15)C(═S)R7+, -(alkylene)q-OC(═O)NR8+R9+, -(alkylene)q-OC(═S)NR8+R9+, -(alkylene)q-SO2NR8+R9+, -(alkylene)q-N(R15)SO2e, -(alkylene)q-N(R15)SO2NR8+R9+, -(alkylene)q-N(R15)C(═O)OR7+, -(alkylene)q-N(R15)C(═S)OR7+, or -(alkylene)q-N(R15)SO2R7+;
wherein alkylene, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more -(alkylene)q-CN, -(alkylene)q-OR7+, -(alkylene)q-S(O)nR7+, -(alkylene)q-NR8+R9+, -(alkylene)q-C(═O)R7+, -(alkylene)q-C(═S)R7+, -(alkylene)q-C(═O)OR7+, -(alkylene)q-OC(═O)R7+, -(alkylene)q-C(═S)OR7+, -(alkylene)q-C(═O)NR8+R9+, -(alkylene)q-C(═S)NR8+R9+, -(alkylene)q-N(R15)C(═O)NR8+R9+, -(alkylene)q-N(R15)C(═S)NR8+R9+, -(alkylene)q-N(R15)C(═O)R7+, -(alkylene)q-N(R15)C(═S)R7+, -(alkylene)q-OC(═O)NR8+R9+, -(alkylene)q-OC(═S)NR8+R9+, -(alkylene)q-SO2NR8+R9+, -(alkylene)q-N(R15)SO2R7+, -(alkylene)q-N(R15)SO2NR8+R9+, -(alkylene)q-N(R15)C(═O)OR7+, -(alkylene)q-N(R15)C(═S)OR7+, or -(alkylene)q-N(R15)SO2R7+;
J and W are independently —CH2—, —N(R8)—, —O—, or —S(═O)v—,
X is —O— or —S(═O)v—
U and U1 are independently CH or N
k at each occurrence is independently 0, 1, 2 or 3;
m is 1, 2 or 3
n is 0, 1 or 2
p is 1, 2 or 3
q at each occurrence is independently 0 or 1
r is 0, 1, 2 or 3;
s is 1, 2 or 3
t is 0, 1 or 2
v at each occurrence is independently 0, 1 or 2

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Alkynyl alcohols as kinase inhibitors

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Alkynyl alcohols as kinase inhibitors

Life of this patent

Abstract

Claims27