US 2010/0063032 A1 · SUBSTITUTED PYRIDO[2,3-D]PYRIMIDINE DERIVATIVES AS CANNABINOID-1 RECEPTOR MODULATORS

Abstract

Novel compounds of the structural formula (I) are antagonists and/or inverse agonists of the Cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the CB1 receptor. The compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, Alzheimer s disease, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson s disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, the treatment of obesity or eating disorders, as well as the treatment of asthma, constipation, chronic intestinal pseudo-obstruction, cirrhosis of the liver, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and the promotion of wakefulness.

A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein:
“a” is:
(1) a single bond when R2 is present and R3 is oxo, or
(2) a double bond when R2 is absent and R3 is not oxo;
Ar1 is selected from:
(1) aryl, and
(2) heteroaryl,
wherein aryl and heteroaryl are unsubstituted or substituted with one, two, three or four substituents selected from R5 and R6;
Ar2 is selected from:
(1) aryl, and
(2) heteroaryl,
wherein aryl and heteroaryl are unsubstituted or substituted with one, two, three or four substituents independently selected from R7 and R8;
R1 is selected from:
(1) C1-10alkyl,
(2) C3-10cycloalkyl,
(3) C3-10cycloalkenyl,
(4) C3-10cycloalkyl-C1-4alkyl,
(5) C3-10cycloalkenyl-C1-4alkyl,
(6) cycloheteroalkyl,
(7) cycloheteroalkyl-C1-4alkyl,
(8) aryl,
(9) aryl-C1-4alkyl,
(10) heteroaryl,
(11) heteroaryl-C1-4alkyl,
(12) —C(O)Re,
(13) —C(O)ORe,
(14) —ORe,
(15) —C(O)NRcRd,
(16) —NRcRd,
(17) —NRcC(O)Rd, and
(18) —C(O)NHS(O)2Re,
wherein each alkyl is unsubstituted or substituted with one to four substituents independently selected from Ra, and each cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to four substituents independently selected from Rb;
R2 is absent or present and selected from:
(1) hydrogen,
(2) C1-10alkyl,
(3) phenyl, and
(4) heteroaryl,
wherein each alkyl, phenyl and heteroaryl is unsubstituted or substituted with one to four substituents independently selected from Ri;
R3 is selected from:
(1) hydrogen,
(2) C1-10alkyl,
(3) C3-10cycloalkyl,
(4) C3-10cycloalkenyl,
(5) C3-10cycloalkyl-C1-4alkyl,
(6) C3-10cycloalkenyl-C1-4alkyl,
(7) cycloheteroalkyl,
(8) cycloheteroalkyl-C1-4alkyl,
(9) aryl,
(10) aryl-C1-4alkyl,
(11) heteroaryl,
(12) heteroaryl-C1-4alkyl,
(13) halogen,
(14) oxo,
(15) —CN,
(16) —C(O)Re,
(17) —C(O)ORe,
(18) —ORe,
(19) —SRe,
(20) —C(O)NRcRd,
(21) —NRcRd,
(22) —NRcRd—NRcRd,
(23) —NRcC(O)Rd,
(24) —NRcNRc—C(O) —NRcNRcRd,
(25) —C(O)NRc—S(O)2Re, and
(26) —NRc—S(O)2Re,
wherein each alkyl is unsubstituted or substituted with one to four substituents independently selected from Ra, and each cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to four substituents independently selected from Rb;
R4 is hydrogen;
each R5, R6, R7, and R8 is independently selected from:
(1) hydrogen,
(2) halogen,
(3) —CN,
(4) C1-6alkyl, unsubstituted or substituted with one, two or three Rf substitutents,
(5) —CF3,
(6) C2-6alkenyl, unsubstituted or substituted with one, two or three Rf substitutents,
(7) cycloalkyl, unsubstituted or substituted with one, two or three Rf substitutents,
(8) cycloalkyl-C1-3alkyl-, unsubstituted or substituted with one, two or three Rf substitutents,
(9) cycloheteroalkyl, unsubstituted or substituted with one, two or three Rf substitutents,
(10) aryl, unsubstituted or substituted with one, two or three Rh substitutents,
(11) aryl-C1-3alkyl-, unsubstituted or substituted on aryl with one, two or three Rh substitutents,
(12) heteroaryl, unsubstituted or substituted with one, two or three Rh substitutents,
(13) heteroaryl-C1-3alkyl-, unsubstituted or substituted with one, two or three Rh substitutents,
(14) —ORd,
(15) —OCF3,
(16) —C(O)Rj,
(17) —CO2Rd,
(18) —C(O)NRcRd,
(19) —SRd,
(20) —S(O)3H,
(21) —S(O)mNRcRd,
(22) —NRcRd,
(23) —NRcC(O)Rd,
(24) —NRcC(O)ORd,
(25) —NRcC(O)NRcRd, and
(26) —NRcS(O)mRd;
each Ra is independently selected from:
(1) —ORd,
(2) —NRcS(O)mRd,
(3) halogen,
(4) —SRd,
(5) —S(O)mNRcRd,
(6) —NRcRd,
(7) —C(O)Rd,
(8) —CO2Rd,
(9) —CN,
(10) —C(O)NRcRd,
(11) —NRcC(O)Rd,
(12) —NRcC(O)ORd,
(13) —NRcC(O)NRcRd,
(14) —O—C1-4alkyl,
(15) —O-aryl,
(16) —CF3, and
(17) —OCF3,
wherein alkyl and aryl are unsubstituted or substituted with one, two or three substituents selected from Rg;
each Rb is independently selected from:
(1) Ra,
(2) halogen,
(3) oxo,
(4) —OH,
(5) C1-10alkyl,
(6) C2-10alkenyl,
(7) cycloalkyl,
(8) cycloalkyl-C1-10 alkyl,
(9) cycloheteroalkyl,
(10) cycloheteroalkyl-C1-10 alkyl,
(11) aryl,
(12) heteroaryl,
(13) aryl-C1-10alkyl,
(14) heteroaryl-C1-10alkyl, and
(15) —C(O)NRcRd,
wherein alkyl and alkenyl moieties are unsubstituted or substituted with one, two, three or four Rh substituents, and cycloalkyl, cycloheteroalkyl, aryl and heteroaryl moieties are unsubstituted or substituted with one, two or three Rh substituents;
Rc and Rd are each independently selected from:
(1) hydrogen,
(2) C1-10alkyl,
(3) C2-10 alkenyl,
(4) cycloalkyl,
(5) cycloalkyl-C1-10alkyl-,
(6) cycloheteroalkyl,
(7) cycloheteroalkyl-C1-10 alkyl-,
(8) aryl,
(9) heteroaryl,
(10) aryl-C1-10alkyl-, and
(11) heteroaryl-C1-10 alkyl-,
wherein alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl are unsubstituted or substituted with one to three substituents selected from Rf;
each Re is independently selected from:
(1) C1-10alkyl,
(2) C0-2alkylC(O)C1-4alkyl,
(3) aryl,
(4) aryl-C1-2alkyl-,
(5) heteroaryl,
(6) heteroaryl-C1-2alkyl-,
(7) cycloalkyl,
(8) cycloalkyl-C1-2alkyl-,
(9) cycloheteroalkyl, and
(10) cycloheteroalkyl-C1-2alkyl-,
wherein alkyl, aryl, heteroaryl, cycloalkyl, and cycloheteroalkyl are unsubstituted or substituted with one, two, or three substituents independently selected from Rh;
each Rf is independently selected from:
(1) halogen,
(2) C1-6alkyl,
(3) 4-methylbenzyl-,
(4) —OH,
(5) —O—C1-4alkyl,
(6) —O-aryl,
(7) benzyloxy-,
(8) -oxo,
(9) —OH,
(10) —OC(O) —C1-6alkyl,
(11) —C(O)O—C1-6alkyl,
(12) —S—C1-4alkyl,
(13) —CN,
(14) —CF3, and
(15) —OCF3,
wherein alkyl, methyl, aryl, benzyl and benzyloxy are unsubstituted or substituted with one, two or three substituents selected from Rg;
each Rg is independently selected from:
(1) halogen,
(2) —O—C1-4alkyl,
(3) —OH,
(4) —S—C1-4alkyl,
(5) —CN,
(6) —CF3, and
(7) —OCF3;
each Rh is independently selected from:
(1) halogen,
(2) oxo,
(3) —OH,
(4) amino,
(5) hydroxy,
(6) C1-6alkyl,
(7) C3-6cycloalkyl,
(8) C2-6cycloheteroalkyl,
(9) —O—C1-4alkyl,
(10) —S—C1-4alkyl,
(11) —CN,
(12) —CF3,
(13) —OCF3,
(14) —C(O)C1-4alkyl,
(15) —CO2C1-4alkyl,
(16) aryl, and
(17) heteroaryl;
each Ri is independently selected from:
(1) —ORd,
(2) —NRcS(O)mRd,
(3) halogen,
(4) —SRd,
(5) —S(O)mNRcRd,
(6) —NRcRd,
(7) —C(O)Rd,
(8) —CO2Rd,
(9) —CN,
(10) —C(O)NRcRd,
(11) —NRcC(O)Rd,
(12) —NRcC(O)ORd,
(13) —NRcC(O)NRcRd,
(14) —CF3,
(15) —OCF3,
(16) aryl, and
(17) heteroaryl;
each Rj is independently selected from:
(1) C1-10alkyl,
(2) C2-10 alkenyl,
(3) cycloalkyl,
(4) cycloalkyl-C1-10alkyl-,
(5) cycloheteroalkyl,
(6) cycloheteroalkyl-C1-10 alkyl-,
(7) aryl,
(8) heteroaryl,
(9) aryl-C1-10alkyl-, and
(10) heteroaryl-C1-10alkyl-;
and
each m is independently selected from 1 and 2.

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Substituted pyrido[2,3-d]pyrimidine derivatives as cannabinoid-1 receptor modulators

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Substituted pyrido[2,3-d]pyrimidine derivatives as cannabinoid-1 receptor modulators

Life of this patent

Abstract

Claims19