Method to treat sickle cell disease

1. A method to treat an acute inflammatory event in a subject with sickle cell disease consisting essentially of administering to a subject in need thereof an effective amount of an A 2A adenosine receptor agonist, wherein the A 2A adenosine receptor agonist is a compound having formula (I):

wherein

Z a is C≡C, O, NH, or NHN═CR 3a ;

Z is CR 3 R 4 R 5 or NR 4 R 5 ;

each R 1 is independently hydrogen, halo, —OR a , —SR a , (C 1 -C 8 )alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C 3 -C 8 )cycloalkyl, heterocycle, heterocycle(C 1 -C 8 )alkylene-, aryl, aryl(C 1 -C 8 )alkylene-, heteroaryl, heteroaryl(C 1 -C 8 )alkylene-, —CO 2 R a , R a C(═O)O—, R a C(═O)—, —OCO 2 R a , R b R c NC(═O)O—, R a OC(═O)N(R b )—, R b R c N—, R b R c NC(═O)—, R a C(═O)N(R b )—, R b R c NC(═O)N(R b )—, R b R c NC(═S)N(R b )—, R a OC(═S)—, R a C(═S)—, —SSR a , R a S(═O)—, R a S(═O) 2 —, or —N═NR b ;

each R 2 is independently hydrogen, halo, (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, heterocycle, heterocycle(C 1 -C 8 )alkylene-, aryl, aryl(C 1 -C 8 )alkylene-, heteroaryl, or heteroaryl(C 1 -C 8 )alkylene-; or

R 1 and R 2 and the atom to which they are attached is C═O, C═S or C═NR d ;

R 4 and R 5 are independently H or (C 1 -C 8 )alkyl; or

R 4 and R 5 together with the atom to which they are attached form a saturated, partially unsaturated, or aromatic ring that is mono-, bi-, or polycyclic having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms optionally having 1, 2, 3, or 4 heteroatoms selected from non-peroxide oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—S(O) 2 —) or amine in the ring;

wherein R 4 and R 5 are independently substituted with 0-3 R 6 groups or any ring comprising R 4 and R 5 is substituted with from 0 to 14 R 6 groups; wherein each R 6 is independently hydrogen, halo, —OR a , —SR a , (C 1 -C 8 )alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C 1 -C 8 )cycloalkyl, (C 6 -C 12 )bicycloalkyl, heterocycle, heterocycle (C 1 -C 8 )alkylene-, aryl, aryl (C 1 -C 8 )alkylene-, heteroaryl, heteroaryl(C 1 -C 8 )alkylene-, —CO 2 R a , R a C(═O)O—, R a C(═O)—, —OCO 2 R a , R b R c NC(═O)O—, R a OC(═O)N(R b )—, R b R C N—, R b R c NC(═O)—, R a C(═O)N(R b )—, R b R c NC(═O)N(R b )—, R b R c NC(═S)N(R b )—, R a OC(═S)—, R a C(═S)—, —SSR a , R a S(═O)—, —NNR b , or two R 6 groups and the atom to which they are attached is C═O, C═S; or two R 6 groups together with the atom or atoms to which they are attached can form a carbocyclic or heterocyclic ring comprising from 1-6 atoms and optionally comprising 1, 2, 3, or 4 heteroatoms selected from non-peroxide oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—S(O) 2 —) or amine in the ring;

R 3 is hydrogen, halo, —OR a , —SR a , (C 1 -C 8 )alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C 3 -C 8 )cycloalkyl, heterocycle, heterocycle(C 1 -C 8 )alkylene-, aryl, aryl(C 1 -C 8 )alkylene-, heteroaryl, heteroaryl(C 1 -C 8 )alkylene-, —CO 2 R a , R a C(═O)O—, R a C(═O)—, —OCO 2 R a , R b R c NC(═O)O—, R a OC(═O)N(R b )—, R b R c N—, R b R c NC(═O)—, R a C(═O)N(R b )—, R b R c NC(═O)N(R b )—, R b R c NC(═S)N(R b )—, R a OC(═S)—, R a C(═S)—, —SSR a , R a S(═O)—, R a S(═O) 2 —, or —NNR b ; or if the ring formed from CR 4 R 5 is aryl or heteroaryl or partially unsaturated then R 3 can be absent;

R 3a is hydrogen, (C 1 -C 8 )alkyl or aryl;

each R 7 is independently hydrogen, (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, aryl, aryl(C 1 -C 8 )alkylene, heteroaryl, or heteroaryl(C 1 -C 8 )alkylene-;

X is —CH 2 OR a , —CO 2 R a , —CH 2 OC(O)R a , —C(O)NR b R c , —CH 2 SR a , —C(S)OR a , —CH 2 OC(S)R a , —C(S)NR b R c , or —CH 2 N(R b )(R c ); or

X is an aromatic ring of the formula:

each Z 1 is non-peroxide oxy (—O—), S(O) 0-2 , —C(R 8 )—, or amine (—NR 8 —), provided that at least one Z 1 is non-peroxide oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—S(O) 2 —) or amine (—NR 8 —);

each R 8 is independently hydrogen, (C 1 -C 8 )alkyl, (C 1 -C 8 )alkenyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 8 )alkylene, (C 3 -C 8 )cycloalkenyl, (C 3 -C 8 )cycloalkenyl(C 1 -C 8 )alkylene, aryl, aryl(C 1 -C 8 )alkylene, heteroaryl, or heteroaryl(C 1 -C 8 )alkylene, wherein any of the alkyl or alkenyl groups of R 8 are optionally interrupted by —O—, —S—, or —N(R a )—;

wherein any of the alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl, groups of R 1 , R 2 , R 3 , R 3a , R 6 , R 7 and R 8 is optionally substituted on carbon with one or more substituents selected from the group consisting of halo, —OR a , —SR a , (C 1 -C 8 )alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C 3 -C 8 )cycloalkyl, (C 6 -C 12 )bicycloalkyl, heterocycle, heterocycle(C 1 -C 8 )alkylene-, aryl, aryloxy, aryl (C 1 -C 8 )alkylene-, heteroaryl, heteroaryl(C 1 -C 8 )alkylene-, —CO 2 R a , R a C(═O)O—, R a C(═O)—, —OCO 2 R a , R b R c NC(═O)O—, R a OC(═O)N(R b )—, R b R c N—, R b R c NC(═O)—, R a C(═O)N(R b )—, R b R c NC(═O)N(R b )—, R b R c NC(═S)N(R b )—, R a OC(═S)—, R a C(═S)—, —SSR a , R a S(═O) p —, R b R c NS(O) p —, and —N═NR b ;

wherein any (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 6 -C 12 )bicycloalkyl, (C 1 -C 8 )alkoxy, (C 1 -C 8 )alkanoyl, (C 1 -C 8 )alkylene, or heterocycle, is optionally partially unsaturated;

each R a , is independently hydrogen, (C 1 -C 12 )alkyl, (C 1 -C 8 )alkoxy-(C 1 -C 8 )alkyl-, (C 1 -C 8 )alkylthio-(C 1 -C 8 )alkyl-, or amino acid,

each R b , and R c is independently hydrogen, (C 1 -C 12 )alkyl, (C 1 -C 8 )alkoxy-(C 1 -C 8 )alkyl-, (C 3 -C 8 )cycloalkyl, (C 1 -C 8 )alkylthio-(C 1 -C 8 )alkyl or amino acid,

alternatively R b and R c , together with the nitrogen to which they are attached, form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;

R d is hydrogen or (C 1 -C 6 )alkyl;

i is 1 or 2

m is 0 to 8 and p is 0 to 2;

provided that m is at least 1 when Z is NR 4 R 5 ; or

a pharmaceutically acceptable salt thereof,

so as to treat an acute inflammatory event in a subject with sickle cell disease.

2. The method of claim 1 , wherein the compound is of formula (Ia):

R 1 is hydrogen, —OH, —CH 2 OH, —OMe, —OAc, —NH 2 , —NHMe, —NMe 2 or —NHAc;

R 2 is hydrogen, (C 1 -C 8 )alkyl, cyclopropyl, cyclohexyl or benzyl;

R 3 is hydrogen, OH, OMe, OAc, NH 2 , NHMe, NMe 2 or NHAc;

CR 4 R 5 or NR 4 R 5 is optionally substituted with 0-2 R 6 and is cyclopentane, cyclohexane, piperidine, dihydro-pyridine, tetrahydro-pyridine, pyridine, piperazine, tetrahydro-pyrazine, dihydro-pyrazine, pyrazine, dihydro-pyrimidine, tetrahydro-pyrimidine, hexahydro-pyrimidine, pyrazine, imidazole, dihydro-imidazole, imidazolidine, pyrazole, dihydro-pyrazole, or pyrazolidine; or

the ring CR 4 R 5 or NR 4 R 5 is optionally substituted with 0-2 R 6 and is selected from the group consisting of:

R 6 is hydrogen, (C 1 -C 8 )alkyl, —OR a , —CO 2 R a , R b R c NC(═O)—, or aryl;

R a and R b are independently hydrogen, (C 3 -C 4 )-cycloalkyl, or (C 1 -C 8 )alkyl;

each R 7 is independently hydrogen, (C 1 -C 8 )alkyl, aryl, aryl(C 1 -C 8 )alkylene, or heteroaryl(C 1 -C 8 )alkylene;

R 8 is methyl, ethyl, propyl, 2-propenyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, —(CH 2 ) 2 CO 2 CH 3 , or —(CH 2 ) 2-3 OH;

X is —CH 2 OR a , —CO 2 R a , —CH 2 OC(O)R a , or —C(O)NR b R c ; or

X is selected from:

m is 0, 1, or 2;

or a pharmaceutically acceptable salt thereof.

3. The method of claim 2 , wherein

R 1 is hydrogen, OH, OMe, or NH 2 ;

R 2 is hydrogen, methyl, ethyl or propyl;

R 3 is hydrogen, OH, OMe, or NH 2 ;

the ring CR 4 R 5 or NR 4 R 5 is selected from the group consisting of:

q is from 0 to 4;

R 6 is hydrogen, (C 1 -C 8 )alkyl, —CO 2 R a , —CO 2 R a , R a C(═O)—, R a C(═O)O—, R b R c N—, R b R c NC(═O)—, or aryl;

R a and R b are independently hydrogen, methyl, ethyl, propyl, butyl, ethylhexyl, cyclopropyl, or cyclobutyl;

N(R 7 ) 2 is amino, methylamino, dimethylamino; ethylamino; pentylamino, diphenylethylamino, (pyridinylmethyl)amino, (pyridinyl)(methyl)amino, diethylamino or benzylamino; and,

R 8 is methyl, ethyl, propyl, or cyclopropyl;

X is —CH 2 OR a or —C(O)NR b R c ; or

X is selected from:

or a pharmaceutically acceptable salt thereof.

4. The method of claim 3 , wherein:

R 1 is hydrogen, OH, or NH 2 ;

R 2 is hydrogen or methyl;

R 3 is hydrogen, OH, or NH 2 ;

the ring CR 4 R 5 or NR 4 R 5 is selected from the group consisting of:

where q is from 0 to 2;

R 6 is hydrogen, methyl, ethyl, t-butyl, phenyl, —CO 2 R a —CONR b R c , or R a C(═O)—;

R b is H;

R a is methyl, ethyl, propyl, butyl, pentyl, ethylhexyl cyclopropyl, or cyclobutyl; —N(R 7 ) 2 is amino, methylamino, dimethylamino; ethylamino; diethylamino or benzylamino;

or a pharmaceutically acceptable salt thereof.

5. The method of claim 4 , wherein:

R 1 is hydrogen or OH;

R 2 is hydrogen;

R 3 is hydrogen or OH;

the ring CR 4 R 5 or NR 4 R 5 is selected from the group consisting of:

R 6 is hydrogen, methyl, ethyl, —CO 2 R a , or —CONR b R c ;

R b is H;

R a is methyl, ethyl, i-propyl, i-butyl, tert-butyl, or cyclopropyl;

N(R 7 ) 2 is amino, or methylamino;

X is —CH 2 OH,

C(O)NHCH 3 , or —C(O)NHCH 2 CH 3 ;

or a pharmaceutically acceptable salt thereof.

6. The method of claim 1 , wherein the ring comprising R 4 and R 5 is 2-methyl cyclohexane, 2,2-dimethylcyclohexane, 2-phenyl cyclohexane, 2-ethylcyclohexane, 2,2-diethylcyclohexane, 2-tert-butyl cyclohexane, 3-methyl cyclohexane, 3,3-dimethylcyclohexane, 4-methyl cyclohexane, 4-ethylcyclohexane, 4-phenyl cyclohexane, 4-tert-butyl cyclohexane, 4-carboxymethyl cyclohexane, 4-carboxyethyl cyclohexane, 3,3,5,5-tetramethyl cyclohexane, 2,4-dimethyl cyclopentane, 4-cyclohexanecarboxylic acid, 4-cyclohexanecarboxylic acid esters, 4-methyloxyalkanoyl-cyclohexane, 4-piperidine-1-carboxylic acid methyl ester, 4-piperidine-1-carboxylic acid tert-butyl ester, 4-piperidine, 4-piperazine-1-carboxylic acid methyl ester, 4-piperidine-1-carboxylic acid tert-butylester, 1-piperidine-4-carboxylic acid methyl ester, 1-piperidine-4-carboxylic acid tert-butyl ester, tert-butylester, 1-piperidine-4-carboxylic acid methyl ester, or 1-piperidine-4-carboxylic acid tert-butyl ester, 3-piperidine-1-carboxylic acid methyl ester, 3-piperidine-1-carboxylic acid tert-butyl ester, 3-piperidine, 3-piperazine-1-carboxylic acid methyl ester, 3-piperidine-1-carboxylic acid tert-butylester, 1-piperidine-3-carboxylic acid methyl ester, or 1-piperidine-3-carboxylic acid tert-butyl ester;

or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 , wherein the A 2A adenosine receptor agonist is

wherein R c is Et; R 7 is H and —(R 1 CH) m —Z is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

8. The method of claim 1 , wherein the A 2A adenosine receptor agonist is

wherein R c is cPr; R 7 is H and —(R 1 CH) m —Z is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

9. The method of claim 7 , wherein R c is Et, R 7 is H and —(R 1 CH) m —Z is

10. The method of claim 1 , wherein the A 2A adenosine receptor agonist is formula (Ib)-(Id) or a pharmaceutically acceptable salt thereof:

11. The method of claim 10 , wherein the A 2A adenosine receptor agonist is selected from:

or a pharmaceutically acceptable salt thereof.