US 2009/0264429 A1 · Aryl - Hydroxyethylamino - Pyrimidines and Triazines as Modulators of Fatty Acid amide Hydrolase

Abstract

Certain aryl-hydroxyethylamino-pyrimidine and triazine compounds are described, which are useful as FAAH inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity, such as anxiety, pain, inflammation, sleep disorders, eating disorders, energy metabolism disorders, and movement disorders (e.g., multiple sclerosis). Methods of synthesizing such compounds are also disclosed.

A compound of Formula (I-A):

wherein:
R1 is —H, —C1-4alkyl, —OC1-4alkyl, —S(O)0-2C1-4alkyl, —CN, —CF3, —N(Ra)Rb, or a monocyclic cycloalkyl group,
where Ra and Rb are each independently —H, —C1-4alkyl optionally substituted with —OH, N(Rm)Rn, where Rm and Rn are —H, C1-4alkyl;
or taken together with the nitrogen of attachment Ra and Rb form a 4-7 membered heterocycloalkyl ring;
Ar1 is a phenyl, napthyl, a 5 or 6 membered monocyclic heteroaryl group with carbon at the point of attachment, or a 9 or 10 membered bicyclic heteroaryl group with carbon at the point of attachment, each unsubstituted or substituted with;
(i) one, two, or three Rc moieties,
where each Rc moiety is independently —C1-4alkyl, —C1-4alkyl-OH, —C1-4alkyl-CN, —CF3, —OH, —OC1-4alkyl, —OCF3, —OCHF2, —OCH2CF3, —S(O)0-2C1-4alkyl, —SCF3, —SO2CF3, —CHO, —COC1-4alkyl, —CO2C1-4alkyl, —CO2H, —N(Rd)Re, —SO2NRdRe, —NRdSO2Re, —C(O)NRdRe, —NO2, —CN, phenyl, pyridyl, or halo,
where Rd and Re are each independently —H or —C1-4alkyl, or taken together Rd and Re with the nitrogen of attachment form a 4-7 membered heterocycloalkyl ring;
or
(ii) two or three Rc moieties where two Rc moieties are adjacent to each other and together form —O(CH2)1-3O— unsubstituted or substituted with one or two fluoro groups, and the third Rc moiety, when present, is —C1-4alkyl, —C1-4alkyl-OH, —C1-4alkyl-CN, —CF3, —OH, —OC1-4alkyl, —OCF3, —OCHF2, —OCH2CF3, —S(O)0-2C1-4alkyl, —SCF3, —SO2CF3, —CHO, —COC1-4alkyl, —CO2C1-4alkyl, —CO2H, —N(Rd)Re, —SO2NRdRe, —NRdSO2Re, —C(O)NRdRe, —NO2, —CN, or halo, where Rd and Re are each independently —H or —C1-4alkyl;
X is N or C(Rf),
where Rf is —H or methyl;
Ar2 is:
(i) a phenyl group substituted with:
(a) one, two, or three Rg moieties each at a meta or para position, and optionally with one or two additional Rg moieties at an ortho position;
where each Rg moiety is independently —C1-4alkyl, —C1-4alkyl-OH, —C1-4alkyl-CN, perhaloalkyl, perhaloalkoxy, —OC1-4alkyl, —OC1-4alkyl-(monocyclic cycloalkyl), —S(O)0-2C1-4alkyl, —SCF3, —SO2CF3, —CHO, —COC1-4alkyl, —CO2C1-4alkyl, —CO2H, —N(Rh)Ri, —SO2NRjRk, —NRhSO2Ri, —C(O)NRjRk, —NO2, —CN, or halo;
or a phenoxy, benzyl, phenethyl, or benzoyl group unsubstituted or substituted with —C1-4alkyl, —OC1-4alkyl, perhaloalkyl, perhaloalkoxy, —NO2, —CN, or halo;
where Rh is —H or —C1-4alkyl;
Ri is —C1-4alkyl or monocyclic cycloalkyl group;
or Rh and Ri taken together with the atoms to which they are attached form a monocyclic heterocycloalkyl ring;
Ri is —H or —C1-4alkyl;
and
Rk is —H, —C1-4alkyl or monocyclic cycloalkyl group;
or Rj and Rk taken together with the atoms to which they are attached form a monocyclic heterocycloalkyl ring;
or
(b) two adjacent Rg moieties together form —O(CH2)1-2O— unsubstituted or substituted with one or two fluoro groups;
(ii) a monocyclic heteroaryl group substituted with one, two, or three Rg moieties, where each Rg moiety is independently or two adjacent Rg moieties together form —O(CH2)1-2O— unsubstituted or substituted with one or two fluoro groups;
or
(iii) a naphthyl or bicyclic heteroaryl group unsubstituted or substituted with one, two, or three Rl moieties;
where each Rl moiety is independently —C1-4alkyl, —OC1-4alkyl, perhaloalkyl, perhaloalkoxy, —NO2, —CN, or halo;
R2 is —H or methyl;
and
R3 is —H or methyl;
provided, however, that Ar2 is not —CHO or para substituted —OCF3 when Ar1 is unsubstituted phenyl;
or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite of said compound.

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Aryl - Hydroxyethylamino - Pyrimidines and Triazines as Modulators of Fatty Acid amide Hydrolase

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Aryl - Hydroxyethylamino - Pyrimidines and Triazines as Modulators of Fatty Acid amide Hydrolase

Life of this patent

Abstract

Claims41