Heteroaryl substituted pyrazinyl-piperazine-piperidines with CXCR3 antagonist activity
View Patent ↗The present application discloses a compound, or enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrug of said compound, or pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound having the general structure shown in Formula 1: and the pharmaceutically acceptable salts, solvates or esters thereof. Also disclosed is a method of treating chemokine mediated diseases, such as, palliative therapy, curative therapy, prophylactic therapy of certain diseases and conditions such as inflammatory diseases (non-limiting example(s) include, psoriasis), autoimmune diseases (non-limiting example(s) include, rheumatoid arthritis, multiple sclerosis), graft rejection (non-limiting example(s) include, allograft rejection, xenograft rejection), infectious diseases (e.g, tuberculoid leprosy), fixed drug eruptions, cutaneous delayed-type hypersensitivity responses, ophthalmic inflammation, type I diabetes, viral meningitis and tumors using a compound of Formula 1.
1. A compound having the structure shown in Formula 1:
or a pharmaceutically acceptable salt thereof wherein:
X is N, or O;
D is selected from the group consisting of pyridyl, furanyl, pyrimidinyl, pyrazinyl, pyrazolyl, isoxazolyl, 1,4-dioxanyl, and thiazolyl; wherein said ring D is unsubstituted or optionally substituted with 1-5 independently selected R 20 moieties;
R 1 and R 2 are independently absent or present, and if present each is independently selected from the group consisting of H, alkyl, hydroxyalkyl, alkoxy, alkenyl, carbonyl, cycloalkyl, alkylcycloalkyl-, hydroxycycloalkyl, cycloalkenyl, alkylaryl, arylalkyl, aryl, amino, alkylamino, amidinyl, alkylamidinyl, carboxamido, cyano, hydroxyl, urea, —N≡CH, ═NCN, —(CH 2 ) q CF 3 , —(CH 2 ) q OH, —(CH 2 ) q OR 31 , —(CH 2 ) q NH 2 , —(CH 2 ) q NHR 31 , —(CH 2 ) q N(R 31 ) 2 , —(CH 2 ) q C(═O)NHR 31 , —(CH 2 ) q SO 2 R 31 , —(CH 2 ) q NHSO 2 R 31 , —(CH 2 ) q SO 2 NHR 31 , —C(═S)N(H)alkyl, —N(H)—S(O) 2 -alkyl, —N(H)C(═O)N(H)-alkyl, —S(O) 2 alkyl, —S(O) 2 N(H)alkyl, —S(O) 2 N(alkyl) 2 , —S(O) 2 aryl, —C(═S)N(H)cycloalkyl, —C(═O)N(H)NH 2 , —C(═O)alkyl, —CH 2 CH 2 Ophenyl, —CH 2 CH(OCH 2 CH 3 ) 2 , —C(═O)NHcyclopropyl, —C(═O)N(H)CH 2 CF 3 , —S(O) 2 CH 2 CF 3 , —S(O) 2 CF 3 , -heteroaryl, heterocyclyl, heterocyclenyl, difluorophenyl, fluorophenylmethylene, trifluoromethylphenylmethylene, cyanophenylmethylene, difluorophenylmethylene, bromophenylmethylene, chlorophenylmethylene, bromochlorophenylmethylene, fluorochlorophenylmethylene, dichlorophenylmethylene, methoxylphenylmethylene, —CH 2 -cyclopropyl, cyclohexylmethylene, aminooxadiazoyl, 5-methyl-isoxazolyl, chloropyridyl,
or alternatively when X is N, the N taken together with the R 1 and R 2 forms a heterocyclyl, heteroaryl or —N═C(NH 2 ) 2 ;
R 3 is selected from the group consisting of alkyl, CF 3 , haloalkyl and halogen;
R 6 is selected from the group consisting of H, —N(R 30 ) 2 , and —N(R 30 )C(═O)N(R 30 ) 2 ;
R 7 and R 8 are H; or alternatively R 7 and R 8 taken together with the carbon atom to which they are shown attached is —C═O—;
R 10 is alkyl;
the R 11 moieties can be the same or different, each being independently H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclenyl, alkylaryl, arylalkyl, hydroxyalkyl, carboxamide, CO 2 H, —(CH 2 ) q OH, —(CH 2 ) q OR 31 , —(CH 2 ) q NHR 31 , —(CH 2 ) q N(R 31 ) 2 , —OR 30 , halogen, or —C(═O)R 31 , or two geminally substituted R 11 moieties taken together with the carbon atom to which they are attached is —C(═O)—;
R 12 is selected from the group consisting of H, alkyl, —CN, —C(═O)N(R 30 ) 2 , —(CH 2 ) q OH, —(CH 2 ) q OR 31 , —(CH 2 ) q NHR 31 , —(CH 2 ) q N(R 31 ) 2 , and —S(O 2 )R 31 ;
the R 20 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, alkylthiocarboxy, alkylheteroaryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aminoalkyl, amidinyl, aralkyl, aralkenyl, aralkoxy, aralkoxycarbonyl, aralkylthio, aryl, aroyl, aryloxy, cyano, cycloalkyl, cycloalkenyl, formyl, guanidinyl, halogen, haloalkyl, haloalkoxy, heteroaryl, heterocyclyl, heterocyclenyl, hydroxyalkyl, hydroxamate, nitro, trifluoromethyl, trifluoromethoxy, —(CH 2 ) q OH, —(CH 2 ) q OR 31 , —(CH 2 ) q NH 2 , —(CH 2 ) q NHR 31 , —(CH 2 ) q N(R 31 ) 2 , —(CH 2 ) q C(═O)NHR 31 , —(CH 2 ) q SO 2 R 31 , —(CH 2 ) q NHSO 2 R 31 , —(CH 2 ) q SO 2 NHR 31 , -alkynylC(R 31 ) 2 OR 31 , —C(═O)R 30 , —C(═O)N(R 30 ) 2 , —C(═NR 30 )NHR 30 , —C(═NOH)N(R 30 ) 2 , —C(═NOR 31 )N(R 30 ) 2 , —C(═O)OR 30 , —N(R 30 ) 2 , —N(R 30 )C(═O)R 31 , —NHC(═O)N(R 30 ) 2 , —N(R 30 )C(═O)OR 31 , —N(R 30 )C(═NCN)N(R 30 ) 2 , —N(R 30 )C(═O)N(R 30 )SO 2 (R 31 ), —N(R 30 )C(═O)N(R 30 ) 2 , —N(R 30 )SO 2 (R 31 ), —N(R 30 )S(O) 2 N(R 30 ) 2 , —OR 30 , —OC(═O)N(R 30 ) 2 , —SR 30 , —SO 2 N(R 30 ) 2 , —SO 2 (R 31 ), —OSO 2 (R 31 ), and —OSi(R 30 ) 3 ; or alternatively two R 20 moieties are linked together to form a five or six membered aryl, cycloalkyl, heterocyclyl, heterocyclenyl, or heteroaryl ring wherein said five or six membered aryl, cycloalkyl, heterocyclyl, heterocyclenyl, or heteroaryl ring is fused to ring D and the fused ring is optionally substituted with 0-4 R 21 moieties;
the R 21 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, alkylthiocarboxy, alkylheteroaryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aminoalkyl, amidinyl, aralkyl, aralkenyl, aralkoxy, aralkoxycarbonyl, aralkylthio, aryl, aroyl, aryloxy, carboxamido, cyano, cycloalkyl, cycloalkenyl, formyl, guanidinyl, halogen, haloalkyl, heteroaryl, heterocyclyl, heterocyclenyl, hydroxyalkyl, hydroxamate, nitro, trifluoromethoxy, —(CH 2 ) q OH, —(CH 2 ) q OR 31 , —(CH 2 ) q NH 2 , —(CH 2 ) q NHR 31 , —(CH 2 ) q N(R 31 ) 2 , —(CH 2 ) q C(═O)NHR 31 , —(CH 2 ) q SO 2 R 31 , —(CH 2 ) q N(H)SO 2 R 31 , —(CH 2 ) q SO 2 NHR 31 , -alkynylC(R 31 ) 2 OR 31 , —C(═O)R 30 , —C(═O)N(R 30 ) 2 , —C(═NR 30 )NHR 30 , —C(═NOH)N(R 30 ) 2 , —C(═NOR 31 )N(R 30 ) 2 , —C(═O)OR 30 , —N(R 30 ) 2 , —N(R 30 )C(═O)R 31 , —NHC(═O)N(R 30 ) 2 , —N(R 30 )C(═O)OR 31 , —N(R 30 )C(═NCN)N(R 30 ) 2 , —N(R 30 )C(═O)N(R 30 )SO 2 (R 31 ), —N(R 30 )C(═O)N(R 30 ) 2 , —N(R 30 )SO 2 (R 31 ), —N(R 30 )S(O) 2 N(R 30 ) 2 , —OR 30 , —OC(═O)N(R 30 ) 2 , —SR 30 , —SO 2 N(R 30 ) 2 , —SO 2 (R 31 ), —OSO 2 (R 31 ), and —OSi(R 30 ) 3 ;
Y is selected from the group consisting of —(CR 13 R 13 ) r — and —C(═O)—;
R 13 is H;
the R 30 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, CN, —(CH 2 ) q OH, —(CH 2 ) q Oalkyl, —(CH 2 ) q Oalkylaryl, —(CH 2 ) q Oaryl, —(CH 2 ) q Oaralkyl, —(CH 2 ) q Ocycloalkyl, —(CH 2 ) q NH 2 , —(CH 2 ) q NHalkyl, —(CH 2 ) q N(alkyl) 2 , —(CH 2 ) q NHalkylaryl, —(CH 2 ) q NHaryl, —(CH 2 ) q NHaralkyl, —(CH 2 ) q NHcycloalkyl, —(CH 2 ) q C(═O)NHalkyl, —(CH 2 ) q C(═O)N(alkyl) 2 , —(CH 2 ) q C(═O)NHalkylaryl, —(CH 2 ) q C(═O)NHaryl, —(CH 2 ) q C(═O)NHaralkyl, —(CH 2 ) q C(═O)NHcycloalkyl, —(CH 2 ) q SO 2 alkyl, —(CH 2 ) q SO 2 alkylaryl, —(CH 2 ) q SO 2 aryl, —(CH 2 ) q SO 2 aralkyl, —(CH 2 ) q SO 2 cycloalkyl, —(CH 2 ) q N(H)SO 2 alkyl, —(CH 2 ) q N(H)SO 2 alkylaryl, —(CH 2 ) q N(H)SO 2 aryl, —(CH 2 ) q N(H)SO 2 aralkyl, —(CH 2 ) q N(H)SO 2 cycloalkyl, —(CH 2 ) q SO 2 NHalkyl, —(CH 2 ) q SO 2 NHalkylaryl, —(CH 2 ) q SO 2 NHaryl, —(CH 2 ) q SO 2 NHaralkyl, —(CH 2 ) q SO 2 NHcycloalkyl, heterocyclenyl, heterocyclyl, and heteroaryl;
the R 31 moieties can be the same or different, each being independently selected from the group consisting of alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, —(CH 2 ) q OH, —(CH 2 ) q Oalkyl, —(CH 2 ) q Oalkylaryl, —(CH 2 ) q Oaryl, —(CH 2 ) q Oaralkyl, —(CH 2 ) q Ocycloalkyl, —(CH 2 ) q NH 2 , —(CH 2 ) q NHalkyl, —(CH 2 ) q N(alkyl) 2 , —(CH 2 ) q NHalkylaryl, —(CH 2 ) q NHaryl, —(CH 2 ) q NHaralkyl, —(CH 2 ) q NHcycloalkyl, —(CH 2 ) q C(═O)NHalkyl, —(CH 2 ) q C(═O)N(alkyl) 2 , —(CH 2 ) q C(═O)NHalkylaryl, —(CH 2 ) q C(═O)NHaryl, —(CH 2 ) q C(═O)NHaralkyl, —(CH 2 ) q C(═O)NHcycloalkyl, —(CH 2 ) q SO 2 alkyl, —(CH 2 ) q SO 2 alkylaryl, —(CH 2 ) q SO 2 aryl, —(CH 2 ) q SO 2 aralkyl, —(CH 2 ) q SO 2 cycloalkyl, —(CH 2 ) q N(H)SO 2 alkyl, —(CH 2 ) q N(H)SO 2 alkylaryl, —(CH 2 ) q N(H)SO 2 aryl, —(CH 2 ) q N(H)SO 2 aralkyl, —(CH 2 ) q N(H)SO 2 cycloalkyl, —(CH 2 ) q ,SO 2 NHalkyl, —(CH 2 ) q SO 2 NHalkylaryl, —(CH 2 ) q SO 2 NHaryl, —(CH 2 ) q SO 2 NHaralkyl, —(CH 2 ) q SO 2 NHcycloalkyl, heterocyclenyl, heterocyclyl, and heteroaryl;
m is 0 to 4;
n is 0 to 4;
each q can be the same or different, each being independently selected from 1 to 5; and
r is 1 to 4;
wherein said aryl of R 1 , R 2 , R 11 , R 20 , R 21 , R 30 , and R 31 is independently an aromatic monocyclic or multicyclic ring system comprising 6 to 14 carbon atoms;
wherein said heteroaryl of R 1 , R 2 , R 11 , R 20 , R 21 , R 30 , and R 31 is an aromatic monocyclic or multicyclic ring system comprising from 5 to 14 ring atoms wherein one or more of the ring atoms of the heteroaryl is nitrogen, oxygen, or sulfur;
wherein said heterocyclyl of R 1 , R 2 , R 11 , R 20 , R 21 , R 30 , and H 31 is a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to 10 ring atoms, wherein one or more of the ring atoms of the heterocyclyl is nitrogen, oxygen, or sulfur;
wherein said heterocyclenyl of R 1 , R 2 , R 11 , R 20 , R 21 , R 30 , and R 31 non-aromatic monocyclic or multicyclic ring system comprising 3 to 10 ring atoms, wherein one or more of the ring atoms of the heterocyclenyl is nitrogen, oxygen, or sulfur, and wherein the heterocyclenyl contains at least one carbon-carbon double bond or carbon-nitrogen double bond;
with the proviso that there are no two adjacent double bonds in any ring, and that when a nitrogen is substituted by two alkyl groups, said two alkyl groups may be optionally joined to each other to form a ring.
2. The compound according to claim 1 , wherein R 1 and R 2 are independently absent or present, and if present each is independently selected from the group consisting of H, alkyl, aryl, amino, alkoxy, hydroxy, cycloalkyl, alkylcycloalkyl-, cycloalkenyl, arylalkyl, amidinyl, alkylamidinyl, carboxamido, heteroaryl, heterocyclyl, heterocyclenyl, urea, —S(O) 2 alkyl, —S(O) 2 N(H)alkyl, —S(O) 2 N(alkyl) 2 , and —C(═S)N(H)cycloalkyl.
3. The compound according to claim 1 , wherein R 1 and R 2 are independently absent or present, and if present each is independently selected from the group consisting of H, alkylaryl, aryl, heteroaryl, —(CH 2 ) q CF 3 , —(CH 2 ) q OH, —(CH 2 ) q OR 31 , —(CH 2 ) q NH 2 , —(CH 2 ) q NHR 31 , —(CH 2 ) q N(R 31 ) 2 , —(CH 2 ) q C(═O)NHR 31 , —(CH 2 ) q SO 2 R 31 , —(CH 2 ) q NHSO 2 R 31 , —(CH 2 ) q SO 2 NHR 31 , —(CH 2 ) q -amidinyl, alkylamidinyl, cyclopropyl, CH 3 -cyclopropyl-, -cyclopropylhydroxyl, cyclobutyl, -cyclobutylhydroxy, cyclopentyl, and cyclopentylhydroxy; and
q is an integer from 1 to 5.
4. The compound according to claim 1 , wherein R 1 and R 2 are independently absent or present, and if present each is independently selected from the group consisting of H, —CH 3 , fluorophenylmethylene, trifluoromethylphenylmethylene, indanyl, cyanophenylmethylene, difluorophenylmethylene, bromophenylmethylene, chlorophenylmethylene, —CH 2 CH 2 Ophenyl, cyclopentyl, bromochlorophenylmethylene, fluorochlorophenylmethylene, dichlorophenylmethylene, phenylmethylene, —(CH 2 ) 3 phenyl, —CH 2 CF 3 , methoxylphenylmethylene, —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —C 2 H 5 , —CH 2 -cyclopropyl, —(CH 2 ) 2 CH 3 , cyclohexylmethylene, cyclohexyl, —CH 2 CH 2 SO 2 CH 3 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 OCH 3 , cyclopropyl, CH 3 -cyclopropyl-, cyclobutyl, HO-cyclobutyl-, isoxazolyl, isoxazoyl, oxadiazoyl, aminooxadiazoyl, —CH 2 CH 2 OH, —CH 2 CH 2 CH 3 , —NH 2 , pyrazolyl, 5-methyl-isoxazolyl, —CH 2 CH(OCH 2 CH 3 ) 2 , —OCH 3 , —NHC(═O)N H 2 , chloropyridyl, pyridylmethylene, —C(═O)NHcyclopropyl, —C(═O)N(H)C 2 H 5 , —C(═O)N(H)CH 2 CF 3 , —C(═O)N(H)C(CH 3 ) 3 , —C(═S)N(H)cyclopropyl, —C(═O)NH 2 , —C(═O)N(H)CH 3 , —S(O) 2 CH 3 , —S(O) 2 N(CH 3 ) 2 , —S(O) 2 CH 2 CH 3 , —C(═O)CH 3 , —S(O) 2 (CH 2 ) 2 CH 3 , —C(═O)N(H)cyclohexyl, —C(═NH)NH 2 , —C(═NH)NH(CH 3 ), —C(═O)N(H)N(H)NH 2 , —C(═O)N(H)CH(CH 3 ) 2 , thiazolyl, —C(═O)N(CH 3 ) 2 , —S(O) 2 CH 2 CF 3 , —S(O) 2 CF 3 ,
or when X is N, the N taken together with the R 1 and R 2 to which X is shown attached, forms an aziridine, an azetidine, a piperidine, or
5. The compound according to claim 1 , wherein R 1 and R 2 are independently absent or present, and if present each is independently selected from the group consisting of H, —CH 3 , —C 2 H 5 , difluorophenylmethylene, cyclopropyl, CH 3 -cyclopropyl, cyclobutyl, hydroxycyclobutyl, dichlorophenylmethylene, —CH(CH 3 ) 2 , —C(CH 3 ) 3 , cyclohexylmethylene, cyclohexyl, isoxazolyl, oxadiazoyl, aminooxadiazoyl, difluorophenyl, —CH 2 CH 2 OH, —CH 2 —CH 2 —N(CH 3 )) 2 , —C(═O)N(H)cyclopropyl, —C(═O)N(H)C 2 H 5 , —C(═O)N(H)CH 2 CF 3 , —C(═O)N(H)CH(CH 3 ) 2 , —C(═O)N(H)C(CH 3 ) 3 , —C(═S)N(H)cyclopropyl, —C(═O)NH 2 , —C(═O)N(H)CH 3 , —S(O) 2 CH 3 , —S(O) 2 N(CH 3 ) 2 S(O) 2 CH 2 CH 3 —C(═O)CH 3 , —S(O) 2 (CH 2 ) 2 CH 3 —C(═O)N(H)cyclohexyl, —C(═NH)NH 2 , —C(═NH)NH(CH 3 ), —C(═O)N(H)NH 2 , thiazolyl,
6. The compound according to claim 1 , wherein R 3 is selected from the group consisting of —CH 3 , —Cl, and CF 3 .
7. The compound according to claim 1 , wherein R 6 is selected from the group consisting of H, —NH 2 , —NHCH 2 cyclopropyl, —NH—C(═O)—N(CH 3 ) 2 , —NHCH 2 -(3,4-difluorophenyl), —NH(CH 2 ) 2 —C(═O)—OCH 3 , and —NH(CH 2 ) 2 OCH 3 .
8. The compound according to claim 1 , wherein R 10 )is selected from the group consisting of —CH 3 , —CH 2 CH 3 and —CH 2 CH 2 CH 3 , and m is 0 - 2.
9. The compound according to claim 1 , wherein R 11 is H, alkyl, or hydroxyalkyl, or two geminal substituted R 11 moieties together with the carbon atom to which they are attached is —C(═O)—.
10. The compound according to claim 9 , wherein R 11 is H or —CH 3 .
11. The compound according to claim 1 , wherein R 12 is selected from the group consisting of H, CN, —C(═O)N(R 30 ) 2 and alkyl.
12. The compound according to claim 11 , wherein R 12 is selected from the group consisting of H, —CH 3 , CN and —CH 2 CH 3 .
13. The compound according to claim 1 , wherein the R 20 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, alkynyl, alkoxy, alkylamino, alkylheteroaryl, alkylsulfinyl, alkoxycarbonyl, aminoalkyl, amidinyl, aralkyl, aralkoxy, aryl, aryloxy, cyano, cycloalkyl, cycloalkenyl, halogen, haloalkyl, haloalkoxy, heteroaryl, heterocyclyl, hydroxyalkyl, trifluoromethyl, trifluoromethoxy, —(CH 2 ) q OR 31 , —(CH 2 ) q NHR 31 , —(CH 2 ) q C(═O)NHR 31 , —(CH 2 ) q SO 2 R 31 , —(CH 2 ) q NHSO 2 R 31 , —(CH 2 ) q SO 2 NHR 31 , -alkynylC(R 31 ) 2 OR 31 , —C(═O)R 30 , —C(═O)N(R 30 ) 2 , —C(═O)OR 30 , —N(R 30 ) 2 , —N(R 30 )C(═O)R 31 ,)—NHC(═O)N(R 30 ) 2 , —N(R 30 )C(═O)OR 31 , —N(R 30 )C(═NCN)N(R 30 ) 2 , —N(R 30 )C(═O)N(R 30 ) 2 , —N(R 30 )SO 2 (R 31 ), —N(R 30 )SO 2 N(R 30 ) 2 , —OR 30 , —OC(═O)N(R 30 ) 2 , —SR 30 , —SO 2 N(R 30 ) 2 , —SO 2 (R 31 ), —OSO 2 (R 31 ), and —OSi(R 30 ) 3 .
14. The compound according to claim 1 , wherein the R 20 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, amino, halogen, CN, CH 3 , CF 3 , OCF 3 , —(CH 2 ) q OR 31 , —(CH 2 ) q NHR 31 , —(CH 2 ) q C(═O)NHR 31 , —(CH 2 ) q SO 2 R 31 , —(CH 2 ) q NHSO 2 R 31 , —(CH 2 ) q SO 2 NHR 31 , -alkynylC(R 31 ) 2 OR 31 , —C(═O)R 30 , —C(═O)OR 30 , —N(R 30 ) 2 , —N(R 30 )C(═O)R 31 , —NHC(═O)N(R 30 ) 2 , —N(R 30 )C(═O)OR 31 , —N(R 30 )C(═NCN)N(R 30 ) 2 , —N(R 30 )C(═O)N(R 30 ) 2 , —OR 30 , —OC(═O)N(R 30 ) 2 , and —OSO 2 (R 31 ).
15. The compound according to claim 1 , wherein two R 20 moieties are linked together to form a five or six membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl or heteroaryl ring wherein said five or six membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl, and heteroaryl ring is fused to ring D and the fused ring is optionally substituted with 0 to 4 R 21 moieties.
16. The compound according to claim 1 , wherein the R 20 moieties can be the same or different, each being independently selected from the group consisting of H, —CN, —CH 3 , —CF 3 , —CH 2 OH, —CO 2 H, —CO 2 CH 3 , —NH 2 , —NHCH 3 , —OCF 3 , —OH, F, CI, Br, —C(═NOH)NH 2 , —OCH 2 CH 2 S(O 2 )CH 3 , —C(═O)NH 2 , —OCH 3 , phenyl, —NHcyclopropyl,
17. The compound according to claim 1 , wherein Y is selected from the group consisting of: —CH 2 —, and —C(═O)—.
18. The compound according to claim 1 , wherein m is 0-3.
19. The compound according to claim 1 , wherein n is 0-2.
20. The compound according to claim 1 , wherein q is 1, 2 or 3.
21. The compound according to claim 1 , wherein r is 1 or 2.
22. The compound according to claim 1 , wherein X is N;
R 1 and R 2 are independently absent or present, and if present each is independently selected from the group consisting of H, alkylaryl, aryl, heteroaryl, —(CH 2 ) q CF 3 , —(CH 2 ), q OH, —(CH 2 ) q OR 31 , —(CH 2 ) q NH 2 , —(CH 2 ) q NHR 31 , —(CH 2 ) q —N(R 31 ) 2 , —(CH 2 ) q C(═O)NHR 31 , —(CH 2 ) q SO 2 R 31 , —(CH 2 ) q NHSO 2 R 31 , —(CH 2 ) q SO 2 NHR 31 , —(CH 2 ) q -amidinyl, amidinyl, alkylamidinyl, cyclopropyl, CH 3 -cyclopropyl, cyclopropylhydroxyl, cyclobutyl, cyclobutylhydroxy, cyclopentyl, and cyclopentylhydroxy;
R 11 is H, alkyl, or hydroxyalkyl, or two geminally substituted R 11 moieties together with the carbon atom to which they are attached is —C(═O)—;
R 12 is selected from the group consisting of H, CN, —C(═O)N(R 30 ) 2 and alkyl;
ring D is substituted with 0-4 R 20 moieties;
the R 20 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, amino, halogen, CN, CH 3 , CF 3 , OCF 3 , —(CH 2 ), q OR 31 , —(CH 2 ) q NHR 31 , —(CH 2 ) q C(═O)NHR 31 , —(CH 2 ) q SO 2 R 31 , —(CH 2 ) q N(H)SO 2 R 31 , —(CH 2 ) q SO 2 NHR 31 , -alkynyIC(R 31 ) 2 OR 31 , —C(═O)R 30 ), —C(═O)OR 30 , —N(R 30 ) 2 , —N(R 30 )C(═O)R 31 ,)—NHC(═O)N(R 30 ) 2 ,)—N(R 30 )C(═O)OR 31 , —N(R 30 )C(═NCN)N(R 30 ) 2 , —N(R 30 )C(═O)N(R 30 ) 2 , —OR 30 , —OC(═O)N(R 30 ) 2 ,
and —OSO 2 (R 31 );
m is 0-2;
n is 0-2;
q is 1 or 2; and
r is 1 or 2.
23. The compound according to claim 1 , represented by the following structural Formula:
wherein the various terms are as defined in claim 1 .
24. A compound selected from the group consisting of
Compound No.
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
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67
68
69
70
71
72
73
74
75
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77
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86
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90
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95
96
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98
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100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
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125
126
127
128
129
130
131
132
133
134
135
136
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138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
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162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
or a pharmaceutically acceptable salt thereof.
25. A compound according to claim 24 , selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
26. A compound according to claim 1 in purified form.
27. A pharmaceutical composition comprising at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable carrier.
28. A pharmaceutical composition comprising at least one compound of claim 24 , or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable carrier.