US 8,546,359 B2Granted

Bicyclic aryl sphingosine 1-phosphate analogs

AssigneeBiogen Idec MA Inc.

InventorsRichard D. Caldwell, Kevin M. Guckian, Gnanasambandam Kumaravel, Wen-Cherng Lee, Edward Yin-Shiang Lin, Xiaogao Liu, Bin Ma, Daniel M. Scott, Zhan Shi, Jermaine Thomas, Arthur G. Taveras, Guo Zhu Zheng

Life of this patent

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Abstract

Compounds that have agonist activity at one or more of the SIP receptors are provided. The compounds are sphingosine analogs that, after phosphorylation, can behave as agonists at SIP receptors.

Claims31

Dependent claims

A method for treatment of a pathological condition or symptom in a mammal, wherein the activity of sphingosine 1-phosphate receptors is implicated and agonism of such activity is desired, comprising administering to said mammal an effective amount of a compound of formula (I):

wherein:
X1 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
X2 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
X3 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
X4 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
X5 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
X6 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
Y is —ORf, —(CRfRg)ORf, —(CRfRg)2ORf, —O—P(O)(ORf)ORg, —OC(O)Rc, —C(O)ORc, —(CRfRg)—P(O)(ORf)ORg, —(C(OH)Rf)—P(O)(ORf)ORg, —S—P(O)(ORf)ORg, tetrazole, —SO2NHRf, —SO3, —CONHRf, —Si(OH)2, or —B(OH)2;
W is —CRfRg—, —NRf—, —O—, —S—, —SO—, or —SO2—;
Cy has the formula:
wherein
Z1 is a bond, —[C(RdRe)]x—, —CRd═CRe—, —O—, —NRf—;
Z2 is a bond, —[C(RdRe)]y—, —CRd═CRe—, —O—, —NRf—;
Z3 is a bond, —[C(RdRe)]z—, —CRd═CRe—, —O—, —NRf—;
each of x, y, and z, independently, is 1 to 3;
each Rd, independently, is H, halo, hydroxy, alkyl, haloalkyl, alkenyl, alkoxy, cycloalkyl, —C(O)NRfRg, —NRfRg, —NRfC(O)Rg, or —SO2NRfRg;
each Re, independently, is H, halo, hydroxy, alkyl, haloalkyl, alkenyl, alkoxy, or cycloalkyl, —C(O)NRfRg, —NRfRg, —NRfC(O)Rg, or —SO2NRfRg;
R1a and R1b, independently, are hydrogen, halo, hydroxy, nitro, cyano, —NRfRg, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, alkoxy, cycloalkylalkoxy, cycloalkenylalkoxy, heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, acyl, cycloalkylacyl, cycloalkenylacyl, heterocyclylacyl, arylacyl, heteroarylacyl, thioalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl;
or R1a and R1b, when taken together, are C2-C5 alkylene optionally terminated by or interrupted by 1 or 2 oxygen atoms, or C2-C5 alkenylene optionally terminated by or interrupted by 1 or 2 oxygen atoms;
R2a and R2b, independently, are hydrogen, halo, hydroxy, nitro, cyano, —NRfRg, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, alkoxy, cycloalkylalkoxy, cycloalkenylalkoxy, heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, acyl, cycloalkylacyl, cycloalkenylacyl, heterocyclylacyl, arylacyl, heteroarylacyl, thioalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl;
or R1a and R2a, when taken together, are C1-C5 alkylene optionally terminated by or interrupted by 1 or 2 oxygen atoms, or C2-C5 alkenylene optionally terminated by or interrupted by 1 or 2 oxygen atoms;
wherein R1a, R1b, R2a, and R2b are each, independently, substituted with 0-5 substituents selected from halo, hydroxy, nitro, cyano, —NRfRg, or —CO2Rf;
L1 is —CH2—, —CHF—, or —CF2—;
Z4 is hydrogen, halo, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, or —ORf;
or Z4 is —CH2— bound to the carbon atom to which Y is bound;
or L1, Z4, Y, and the atoms to which they are bound form a 4-7 membered cycloalkyl group or a 4-7 membered heterocyclyl group having 1 or 2 heteroatoms selected from O and N;
Ra is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl;
wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, —CN, —CHO, —CF3, —OH, —NO2, alkyl, —OCF3, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
Rb is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl;
wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, —CN, —CHO, —CF3, —OH, —NO2, alkyl, —OCF3, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
or Rb and Z4 are taken to together to form —C(O)O— or ═C(Rf)O—;
Rc is alkyl, aryl, trifluoromethyl, methylsulfonyl, trifluoromethylsulfonyl, p-tolylsulfonyl, or a group selected such that —OCORc is a leaving group;
each Rf, independently, is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl;
wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, —CN, —CHO, —CF3, —OH, —NO2, alkyl, —OCF3, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
each Rg, independently, is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl;
wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, —CN, —CHO, —CF3, —OH, —NO2, alkyl, —OCF3, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
or a pharmaceutically acceptable salt or prodrug thereof.

34 more elements

wherein
X1 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
X2 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
X3 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
X4 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
X5 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
X6 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
Y is —ORf, —(CRfRg)ORf, —(CRfRg)2ORf, —O—P(O)(ORf)ORg, —OC(O)Rc, —C(O)ORc, —(CRfRg)—P(O)(ORf)ORg, —(C(OH)Rf)—P(O)(ORf)ORg, —S—P(O)(ORf)ORg, tetrazole, —SO2NHRf, —SO3, —CONHRf, —Si(OH)2, or —B(OH)2;
W is —CRfRg—, —NRf—, —O—, —S—, —SO—, or —SO2—;
Z4 is hydrogen, halo, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, or —ORf;
or Z4 is —CH2— bound to the carbon atom to which Y is bound;
or Z4, Y, and the atoms to which they are bound form a 4-7 membered cycloalkyl group or a 4-7 membered heterocyclyl group having 1 or 2 heteroatoms selected from O and N;
Rc is alkyl, aryl, trifluoromethyl, methylsulfonyl, trifluoromethylsulfonyl, p-tolylsulfonyl, or a group selected such that —OCORc is a leaving group;
each Rf, independently, is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl;
wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, —CN, —CHO, —CF3, —OH, —NO2, alkyl, —OCF3, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
each Rg, independently, is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl;
wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, —CN, —CHO, —CF3, —OH, —NO2, alkyl, —OCF3, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
R1a is hydrogen, halo, hydroxy, nitro, cyano, —NRfRg, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, alkoxy, cycloalkylalkoxy, cycloalkenylalkoxy, heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, acyl, cycloalkylacyl, cycloalkenylacyl, heterocyclylacyl, arylacyl, heteroarylacyl, thioalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl;
Z1 is a bond, —[C(RdRe)]x—, or —CRd═CRe—;
Z2 is a bond, —[C(RdRe)]y—, or —CRd═CRe—;
each of x and y independently, is 1 to 3;
each Rd, independently, is hydrogen, halo, hydroxy, alkyl, alkenyl, alkoxy, or cycloalkyl;
each Re, independently, is hydrogen, halo, hydroxy, alkyl, alkenyl, alkoxy, or cycloalkyl;
or a pharmaceutically acceptable salt or prodrug thereof.

21 more elements

(R)-2-amino-2-(6-(cis-4-butylcyclohexyloxy)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(4-butylcyclohexyloxy)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(trans-4-butylcyclohexyloxy)naphthalen-2-yl)propan-1-ol;
2-amino-2-(6-(cis-4-butylcyclohexyloxy)naphthalen-2-yl)propane-1,3-diol;
(R)-2-amino-2-(6-(cis-4-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(cis-4-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)propan-1-phosphoric acid;
(R)-2-amino-2-(6-(cis-4-butylcyclohexyloxy)naphthalen-2-yl)propyl dihydrogen phosphate;
(R)-2-amino-2-(6-(trans-4-butylcyclohexyloxy)naphthalen-2-yl)propyl dihydrogen phosphate;
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)propyl dihydrogen phosphate;
(R)-2-amino-2-(6-(cis-4-(4-(pentan-3-yloxy)phenyl)cyclohexyloxy)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(cis-4-(4-isopropoxyphenyl)cyclohexyloxy)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(cis-4-(4-methoxyphenyl)cyclohexyloxy)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(cis-4-phenylcyclohexyloxy)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(cis-4-phenylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-{6-[trans-4-(1,1-dimethyl-propyl)-cyclohexyloxy]-5-trifluoromethyl-naphthalen-2-yl}-propan-1-ol;
(R)-2-amino-2-(6-(4-pentylcyclohexyloxy)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(4-propylcyclohexyloxy)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(cis-4-methylcyclohexyloxy)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(cis-4-ethylcyclohexyloxy)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(4,4-dimethylcyclohexyloxy)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)propan-1-ol;
2-amino-2-[6-(cis-4-butylcyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-propane-1,3-diol;
2-amino-2-[6-(cis-4-butylcyclohexyloxy)-5-iodo-naphthalen-2-yl]-propane-1,3-diol;
2-amino-2-[6-(trans-4-tert-butylcyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-propane-1,3-diol;
2-amino-2-[6-(trans-4-tert-butyl-cyclohexyloxy)-naphthalen-2-yl]-propane-1,3-diol;
2-amino-2-[6-(trans-4-tert-butyl-cyclohexyloxy)-5-iodo-naphthalen-2-yl]-propane-1,3-diol;
2-amino-2-(6-trans-[3-(benzyloxymethyl)cyclobutoxy)]naphthalen-2-yl)propane-1,3-diol;
2-amino-2-(6-cis-[3-(benzyloxymethyl)cyclobutoxy)]naphthalen-2-yl)propane-1,3-diol;
2-amino-2-[6-(3-trans-benzyloxymethylcyclobutoxy)-5-(trifluoromethyl)naphthalen-2-yl)]propane-1,3-diol;
2-amino-2-[6-(3-cis-benzyloxymethylcyclobutoxy)-5-(trifluoromethyl)naphthalen-2-yl)]propane-1,3-diol;
(R)-2-amino-2-[6-(3-trans-benzyloxymethylcyclobutoxy)naphthalen-2-yl)]propan-1-ol;
(R)-2-amino-2-[6-(3-cis-benzyloxymethylcyclobutoxy)naphthalen-2-yl)]propan-1-ol;
(R)-2-amino-2-[6-(4-trans-tert-pentylcyclohexyloxy)naphthalen-2-yl]propan-1-ol;
(R)-2-amino-2-[6-(4-cis-tert-pentylcyclohexyloxy)naphthalen-2-yl]propan-1-ol;
(R)-2-amino-2-[6-(3-cis-benzyloxymethylcyclobutoxy)-5-trifluoromethylnaphthalen-2-yl)]propan-1-ol;
2-amino-2-[6-(3-cis-(benzyloxymethylcyclobutoxy)naphthalen-2-yl]-3-hydroxypropyl dihydrogen phosphate;
(R)-2-amino-2-{6-[trans-4-(1,1-dimethyl-propyl)-cyclohexyloxy]naphthalen-2-yl}-propan-1-ol;
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-methoxynaphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(trans-4-butyl-cyclohexyloxy)-5-trifluoromethylnaphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(trans-4-butyl-cyclohexyloxy)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(trans-4-trifluoromethylcyclohexyloxy)-5-fluoronaphthalen-2-yl)propan-1-ol;
(R)-2-Amino-2-[6-(decahydro-naphthalen-2-yloxy)-naphthalen-2-yl]-propan-1-ol;
(R)-2-Amino-2-[6-(bicyclohexyl-4-yloxy)-naphthalen-2-yl]-propan-1-ol;
(R)-2-Amino-2-[6-(4-isopropyl-cyclohexyloxy)-naphthalen-2-yl]-propan-1-ol;
(R)-2-Amino-2-[6-(4-cyclopentyl-cyclohexyloxy)-naphthalen-2-yl]-propan-1-ol;
(R)-2-Amino-2-[6-(4-sec-butyl-cyclohexyloxy)-naphthalen-2-yl]-propan-1-ol;
(R)-2-Amino-2-[6-(cis-4-cyclopentyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-propan-1-ol;
(R)-2-Amino-2-[6-(trans-4-cyclopentyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-propan-1-ol;
Phosphoric acid mono-{(R)-2-amino-2-[6-(4-cyclopentyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-propyl}ester;
2-Amino-2-[5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-propane-1,3-diol;
(R)-2-[6-(4-tert-butyl-cyclohexyloxy)-naphthalen-2-yl]-2-methylamino-propan-1-ol;
phosphoric acid mono-{(R)-2-amino-2-{6-[4-(1,1-dimethylpropyl)-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-propyl}Ester;
phosphoric acid mono-{(R)-2-amino-2-[6-(4-tert-butyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-propyl}Ester;
(S)-2-amino-2-[6-(4-trans-tert-butyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-propan-1-ol;
(S)-4-[6-(4-cis-tert-butyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one;
(S)-4-[6-(4-cis-tert-butyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-4-methyl-oxazolidin-2-one;
(S)-2-amino-2-[6-(4-cis-tert-butyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-propan-1-ol;
(R)-4-(6-hydroxy-5-(trifluoromethyl)naphthalen-2-yl)-4-methyloxazolidin-2-one;
(R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)-4-methyloxazolidin-2-one;
(R)-2-amino-2-(6-((4-tert-butylcyclohexyl)methyl)naphthalen-2-yl)propan-1-ol;
3-(6-(trans-4-tert-Butylcyclohexyloxy)naphthalen-2-yl)oxetan-3-amine;
3-(6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)oxetan-3-amine;
(R)-2-Amino-2-(6-(cis-4-cyclohexylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)propan-1-ol;
(R)-2-Amino-2-(6-(trans-4-cyclohexylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(trans-4-cyclohexylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl dihydrogen phosphate;
(R)-2-Amino-2-(6-(cis-4-isopropylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)propan-1-ol;
(R)-2-Amino-2-(6-(trans-4-isopropylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)propan-1-ol;
(R)-2-Amino-2-(6-(trans-4-(1,1-difluoroethyl)cyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl dihydrogen phosphate;
4 amino-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)pentanoic acid;
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-cyclopropylnaphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-methylnaphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-vinylnaphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(methylsulfonyl)phenyl)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(pyrimidin-5-yl)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-ethoxyphenyl)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-phenylnaphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(3-chlorophenyl)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-chlorophenyl)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-chloronaphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(5-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5,7,8-trichloronaphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-fluoronaphthalen-2-yl)propan-1-ol;
2-amino-2-(6-trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)-3-hydroxypropyl dihydrogen phosphate Enantiomer 1;
2-amino-2-(6-trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)-3-hydroxypropyl dihydrogen phosphate Enantiomer 2;
(R)-4-Methyl-4-[6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-oxazolidin-2-one;
(R)-4-Methyl-4-[6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-oxazolidin-2-one;
(R)-4-Methyl-4-[6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-oxazolidin-2-one;
(R)-2-Amino-2-[6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-propan-1-ol;
(R)-2-Amino-2-[6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-propan-1-ol;
Phosphoric acid mono-{(R)-2-amino-2-[6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-propyl}Ester;
(R)-2-Amino-2-[5-trifluoromethyl-6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-propan-1-ol;
Phosphoric acid mono-{(R)-2-amino-2-[5-trifluoromethyl-6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-propyl}Ester;
(R)-2-Amino-2-[6-(4-pentyl-cyclohexyloxy)-naphthalen-2-yl]-propan-1-ol;
(R)-2-Amino-2-[6-(cis-4-pentyl-cyclohexyloxy)-naphthalen-2-yl]-propan-1-ol;
(R)-2-Amino-2-[6-(trans-4-pentyl-cyclohexyloxy)-naphthalen-2-yl]-propan-1-ol;
2-[6-(trans-4-tert-Butyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-propan-1-ol;
2-Amino-2-[6-(trans-4-tert-butyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-propan-1-ol;
4-Amino-4-[6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid;
4-Amino-4-[6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid;
4-Amino-4-[5-trifluoromethyl-6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid;
4-Amino-4-[5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid;
(R)-2-amino-2-(6-(trans-4-(1,1-difluoroethyl)cyclohexyloxy)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(trans-4-(1,1-difluoropropyl)cyclohexyloxy)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(trans-4-(1,1-difluorobutyl)cyclohexyloxy)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(cis-4-(1,1-difluoroethyl)cyclohexyloxy)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(cis-4-(1,1-difluoropropyl)cyclohexyloxy)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(cis-4-(1,1-difluorobutyl)cyclohexyloxy)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(trans-4-(1,1-difluoroethyl)cyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(trans-4-(1,1-difluoropropyl)cyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)propan-1-ol;
(R)-2-amino-2-(6-(cis-4-tert-butylcyclohexyloxy)naphthalen-2-yl)propan-1-ol;
or a pharmaceutically acceptable salt or prodrug thereof.

112 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/608,227Filed 10 Sep 2012 · division
Priority: 30 Oct 2008
Published: US 2013/0059821 A17 Mar 2013
Granted: 1 Oct 2013
Term ends: Not estimatedThe source records don’t support an estimate.

Classification26 codes

A61K 31/135
Amines: having aromatic rings , e.g. ketamine, nortriptyline
A61K 31/27
Esters, e.g. nitroglycerine, selenocyanates: of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics

Family

Application61/109,718Us provisional application · filed 30 Oct 2008
Application12/588,883Parent of this division · filed 30 Oct 2009
US 2013/0059821 A1Pre-grant publication · published 7 Mar 2013
US 8,269,043 B2Parent of this division
US 2010/0160258 A1Published application
US 8,546,359 B2This patent

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

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Abstract

Compounds that have agonist activity at one or more of the SIP receptors are provided. The compounds are sphingosine analogs that, after phosphorylation, can behave as agonists at SIP receptors.

wherein:
X1 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
X2 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
X3 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
X4 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
X5 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
X6 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NRfRg, —N(Rf)SO2Rg, —SO2Rf, —SO2NRfRg, —CO2Rf, trialkylamino, aryl, or heteroaryl;
Y is —ORf, —(CRfRg)ORf, —(CRfRg)2ORf, —O—P(O)(ORf)ORg, —OC(O)Rc, —C(O)ORc, —(CRfRg)—P(O)(ORf)ORg, —(C(OH)Rf)—P(O)(ORf)ORg, —S—P(O)(ORf)ORg, tetrazole, —SO2NHRf, —SO3, —CONHRf, —Si(OH)2, or —B(OH)2;
W is —CRfRg—, —NRf—, —O—, —S—, —SO—, or —SO2—;
Cy has the formula:
wherein
Z1 is a bond, —[C(RdRe)]x—, —CRd═CRe—, —O—, —NRf—;
Z2 is a bond, —[C(RdRe)]y—, —CRd═CRe—, —O—, —NRf—;
Z3 is a bond, —[C(RdRe)]z—, —CRd═CRe—, —O—, —NRf—;
each of x, y, and z, independently, is 1 to 3;
each Rd, independently, is H, halo, hydroxy, alkyl, haloalkyl, alkenyl, alkoxy, cycloalkyl, —C(O)NRfRg, —NRfRg, —NRfC(O)Rg, or —SO2NRfRg;
each Re, independently, is H, halo, hydroxy, alkyl, haloalkyl, alkenyl, alkoxy, or cycloalkyl, —C(O)NRfRg, —NRfRg, —NRfC(O)Rg, or —SO2NRfRg;
R1a and R1b, independently, are hydrogen, halo, hydroxy, nitro, cyano, —NRfRg, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, alkoxy, cycloalkylalkoxy, cycloalkenylalkoxy, heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, acyl, cycloalkylacyl, cycloalkenylacyl, heterocyclylacyl, arylacyl, heteroarylacyl, thioalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl;
or R1a and R1b, when taken together, are C2-C5 alkylene optionally terminated by or interrupted by 1 or 2 oxygen atoms, or C2-C5 alkenylene optionally terminated by or interrupted by 1 or 2 oxygen atoms;
R2a and R2b, independently, are hydrogen, halo, hydroxy, nitro, cyano, —NRfRg, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, alkoxy, cycloalkylalkoxy, cycloalkenylalkoxy, heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, acyl, cycloalkylacyl, cycloalkenylacyl, heterocyclylacyl, arylacyl, heteroarylacyl, thioalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl;
or R1a and R2a, when taken together, are C1-C5 alkylene optionally terminated by or interrupted by 1 or 2 oxygen atoms, or C2-C5 alkenylene optionally terminated by or interrupted by 1 or 2 oxygen atoms;
wherein R1a, R1b, R2a, and R2b are each, independently, substituted with 0-5 substituents selected from halo, hydroxy, nitro, cyano, —NRfRg, or —CO2Rf;
L1 is —CH2—, —CHF—, or —CF2—;
Z4 is hydrogen, halo, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, or —ORf;
or Z4 is —CH2— bound to the carbon atom to which Y is bound;
or L1, Z4, Y, and the atoms to which they are bound form a 4-7 membered cycloalkyl group or a 4-7 membered heterocyclyl group having 1 or 2 heteroatoms selected from O and N;
Ra is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl;
wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, —CN, —CHO, —CF3, —OH, —NO2, alkyl, —OCF3, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
Rb is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl;
wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, —CN, —CHO, —CF3, —OH, —NO2, alkyl, —OCF3, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
or Rb and Z4 are taken to together to form —C(O)O— or ═C(Rf)O—;
Rc is alkyl, aryl, trifluoromethyl, methylsulfonyl, trifluoromethylsulfonyl, p-tolylsulfonyl, or a group selected such that —OCORc is a leaving group;
each Rf, independently, is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl;
wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, —CN, —CHO, —CF3, —OH, —NO2, alkyl, —OCF3, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
each Rg, independently, is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl;
wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, —CN, —CHO, —CF3, —OH, —NO2, alkyl, —OCF3, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
or a pharmaceutically acceptable salt or prodrug thereof.

34 more elements

Facts

Application

13/608,227Filed 10 Sep 2012 · division

Priority

30 Oct 2008

Published

US 2013/0059821 A17 Mar 2013

Granted

1 Oct 2013

Term ends

Not estimatedThe source records don’t support an estimate.

Classification26 codes

A61K 31/135
Amines: having aromatic rings , e.g. ketamine, nortriptyline
A61K 31/27
Esters, e.g. nitroglycerine, selenocyanates: of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics

Family

Application61/109,718Us provisional application · filed 30 Oct 2008

Application12/588,883Parent of this division · filed 30 Oct 2009

US 2013/0059821 A1Pre-grant publication · published 7 Mar 2013

US 8,269,043 B2Parent of this division

US 2010/0160258 A1Published application

US 8,546,359 B2This patent

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