US 7,741,328 B2Granted

Heteroaryl, heterocyclic and aryl compounds which inhibit leukocyte adhesion mediated by VLA-4

AssigneesElan Pharmaceuticals, Inc., Wyeth

InventorsAndrei W. Konradi, Christopher Semko, Ying-Zi Xu

Life of this patent

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Abstract

Disclosed are compounds which bind VLA-4. Certain of these compounds also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a mammalian patient, e.g., human, such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

Claims10

Dependent claims

A compound of formula IIa:

or a pharmaceutically acceptable salt thereof,
wherein
ring A forms a pyrimidine ring, optionally substituted with 1 or 2 substituents selected from the group consisting of R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, alkoxy, substituted alkoxy, amino, substituted amino and halogen,
R3 is —(CH2)x—Ar—R9, wherein
Ar is R107 or R109;
x is an integer from 0 to 4;
and
R9 is selected from the group consisting of acyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, oxycarbonylamino, thioamidino, thiocarbonylamino, aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylamino and oxysulfonyl;
R3′ is hydrogen;
Q is —NR4—, wherein R4 is hydrogen or R101;
R5 is selected from the group consisting of R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111, R112, R115 and R116;
R6 is selected from the group consisting of hydrogen, R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R115 and R116;
and
X is selected from the group consisting of hydroxyl, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, cycloalkoxy, substituted cycloalkoxy, cycloalkenoxy, substituted cycloalkenoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy and —NR″R″, wherein each R″ is independently selected from the group consisting of hydrogen, R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111 and R112,
wherein
R101 is alkyl of from 1 to 10 carbon atoms;
R102 is substituted alkyl of from 1 to 10 carbon atoms, having from 1 to 5 substituents selected from the group consisting of
(1) R200;
(2) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(3) amino groups blocked by blocking groups selected from the group consisting of tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(4) R300;
R103 is cycloalkyl of from 3 to 8 carbon atoms;
R104 is substituted cycloalkyl of from 3 to 8 carbon atoms, having from 1 to 5 substituents selected from the group consisting of
(1) R200;
(2) oxo (═O);
(3) thioxo (═S);
(4) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(5) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(6) R300;
R105 is heterocyclic referring to a saturated or unsaturated group having from 1 to 10 carbon atoms and from 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen, and having a single ring or multiple fused rings, wherein in fused ring systems one or more of the rings can be aryl (R107) or heteroaryl (R109);
R106 is substituted heterocyclic of from 1 to 10 carbon atoms and from 1 to 4 heteroatoms, substituted with from 1 to 3 substituents selected from the group consisting of
(1) R200;
(2) oxo (═O);
(3) thioxo (═S);
(4) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(5) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(6) R300;
R107 is aryl, wherein aryl is an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring or multiple condensed rings, wherein the condensed rings may or may not be aromatic;
R108 is substituted aryl, wherein substituted aryl is aryl substituted with from 1 to 3 substituents selected from the group consisting of
(1) R201;
(2) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R105, R106, R107, R108, R109 and R110;
(3) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(4) —SO2NRR;
R109 is heteroaryl of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring or oxides thereof, having a single ring or multiple condensed rings;
R110 is substituted heteroaryl of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, substituted with from 1 to 3 substituents selected from the group consisting of
(1) R201;
(2) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(3) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(4) —SO2NRR;
R111 is alkenyl of from 2 to 10 carbon atoms and from 1 to 2 sites of alkenyl unsaturation;
R112 is substituted alkenyl, wherein substituted alkenyl is alkenyl substituted with from 1 to 5 substituents selected from the group consisting of
(1) R200;
(2) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(3) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(4) R300;
R113 is alkynyl of from 2 to 10 carbon atoms and from 1 to 2 sites of alkynyl unsaturation;
R114 is substituted alkynyl, wherein substituted alkynyl is alkynyl substituted with from 1 to 5 substituents selected from the group consisting of
(1) R200;
(2) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(3) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(4) R300;
R115 is cycloalkenyl, wherein cycloalkenyl is a cyclic alkenyl group of from 3 to 8 carbon atoms having single or multiple unsaturation, and which is not aromatic;
R116 is substituted cycloalkenyl of from 3 to 8 carbon atoms, having from 1 to 5 substituents selected from the group consisting of
(1) R200;
(2) oxo (═O);
(3) thioxo (═S);
and
(4) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(5) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(6) R300;
wherein
R200 is a member selected from
(1) alkoxy;
(2) substituted alkoxy;
(3) acyl;
(4) acylamino;
(5) thiocarbonylamino;
(6) acyloxy;
(7) amino;
(8) amidino;
(9) alkylamidino wherein alkyl is R101;
(10) thioamidino;
(11) aminoacyl;
(12) aminocarbonylamino;
(13) aminothiocarbonylamino;
(14) aminocarbonyloxy;
(15) R107;
(16) R108;
(17) aryloxy;
(18) substituted aryloxy;
(19) aryloxyaryl;
(20) substituted aryloxyaryl;
(21) halogen;
(22) hydroxyl;
(23) cyano;
(24) nitro;
(25) carboxyl;
(26) carboxylalkyl wherein alkyl is R101;
(27) carboxyl-substituted alkyl wherein substituted alkyl is R102;
(28) carboxyl-cycloalkyl wherein cycloalkyl is R103;
(29) carboxyl-substituted cycloalkyl wherein substituted cycloalkyl is R104;
(30) carboxylaryl wherein aryl is R107;
(31) carboxyl-substituted aryl wherein substituted aryl is R108;
(32) carboxylheteroaryl wherein heteroaryl is R109;
(33) carboxyl-substituted heteroaryl wherein substituted heteroaryl is R110;
(34) carboxylheterocyclic wherein heterocyclic is R105;
(35) carboxyl-substituted heterocyclic wherein substituted heterocyclic is R106;
(36) R103;
(36) R104;
(38) guanidino;
(39) guanidinosulfone;
(40) thiol having the formula —SH;
(41) thioaryl;
(42) substituted thioalkyl;
(43) thioaryl;
(44) substituted thioaryl;
(45) thiocycloalkyl;
(46) substituted thiocycloalkyl;
(47) thioheteroaryl;
(48) substituted thioheteroaryl;
(49) thioheterocyclic;
(50) substituted thioheterocyclic;
(51) R109;
(52) R110;
(53) R105;
(54) R106;
(55) cycloalkoxy;
(56) substituted cycloalkoxy;
(57) heteroaryloxy;
(58) substituted heteroaryloxy;
(59) heterocyclyloxy;
(60) substituted heterocyclyloxy;
(61) oxycarbonylamino;
(62) oxythiocarbonylamino;
(63) —OS(O)2-alkyl, wherein alkyl is R101;
(64) —OS(O)2-substituted alkyl wherein substituted alkyl is R102;
(65) —OS(O)2-aryl, wherein aryl is R107;
(66) —OS(O)2-substituted aryl wherein substituted aryl is R108;
(67) —OS(O)2-heteroaryl wherein heteroaryl is R109;
(68) —OS(O)2-substituted heteroaryl wherein substituted heteroaryl is R110;
(69) —OS(O)2-heterocyclic wherein heterocyclic is R105;
(70) —OS(O)2-substituted heterocyclic wherein substituted heterocyclic is R106;
(71) —NRR where R is hydrogen or R101;
(72) —NRS(O)2-alkyl, wherein alkyl is R101;
(73) —NRS(O)2-substituted alkyl wherein substituted alkyl is R102;
(74) —NRS(O)2-aryl, wherein aryl is R107;
(75) —NRS(O)2-substituted aryl wherein substituted aryl is R108;
(76) —NRS(O)2-heteroaryl wherein heteroaryl is R109;
(77) —NRS(O)2-substituted heteroaryl wherein substituted heteroaryl is R110;
(78) —NRS(O)2-heterocyclic wherein heterocyclic is R105;
(79) —NRS(O)2-substituted heterocyclic wherein substituted heterocyclic is R106;
(80) —NRS(O)2—NR-alkyl, wherein alkyl is R101;
(81) —NRS(O)2—NR-substituted alkyl wherein substituted alkyl is R102;
(82) —NRS(O)2—NR-aryl, wherein aryl is R107;
(83) —NRS(O)2—NR-substituted aryl wherein substituted aryl is R108;
(84) —NRS(O)2—NR-heteroaryl wherein heteroaryl is R109;
(85) —NRS(O)2—NR-substituted heteroaryl wherein substituted heteroaryl is R110;
(86) —NRS(O)2—NR-heterocyclic wherein heterocyclic is R105;
(87) —NRS(O)2—NR-substituted heterocyclic wherein substituted heterocyclic is R106,
(88) mono- and di-alkylamino, wherein alkyl is R101;
(89) mono- and di-(substituted alkyl)amino, wherein substituted alkyl is R102;
(90) mono- and di-arylamino wherein aryl is R107;
(91) mono- and di-substituted arylamino wherein substituted aryl is R108;
(92) mono- and di-heteroarylamino wherein heteroaryl is R109;
(93) mono- and di-substituted heteroarylamino wherein substituted heteroaryl is R110;
(94) mono- and di-heterocyclic amino wherein heterocyclic is R105;
and
(95) mono- and di-substituted heterocyclic amino wherein substituted heterocyclic is R106;
R201 is a member selected from
(1) hydroxyl;
(2) acyl;
(3) acylamino;
(4) thiocarbonylamino;
(5) acyloxy;
(6) R101;
(7) R102;
(8) alkoxy;
(9) substituted alkoxy;
(10) R111;
(11) R112;
(12) R113;
(13) R114;
(14) amidino;
(15) alkylamidino, wherein alkyl is R101;
(16) thioamidino;
(17) amino;
(18) aminoacyl;
(19) aminocarbonyloxy;
(20) aminocarbonylamino;
(21) aminothiocarbonylamino;
(22) R107;
(23) R108;
(24) aryloxy;
(25) substituted aryloxy;
(26) cycloalkoxy;
(27) substituted cycloalkoxy;
(28) heteroaryloxy;
(29) substituted heteroaryloxy;
(30) heterocyclyloxy;
(31) substituted heterocyclyloxy;
(32) carboxyl;
(33) carboxylalkyl wherein alkyl is R101;
(34) carboxyl-substituted alkyl wherein substituted alkyl is R102;
(35) carboxyl-cycloalkyl wherein cycloalkyl is R103;
(36) carboxyl-substituted cycloalkyl wherein substituted cycloalkyl is R104;
(37) carboxylaryl wherein aryl is R107;
(38) carboxyl-substituted aryl wherein substituted aryl is R108;
(39) carboxylheteroaryl wherein heteroaryl is R109;
(40) carboxyl-substituted heteroaryl wherein substituted heteroaryl is R110;
(41) carboxylheterocyclic wherein heterocyclic is R105;
(42) carboxyl-substituted heterocyclic wherein substituted heterocyclic is R106;
(43) carboxylamido;
(44) cyano;
(45) thiol having the formula —SH;
(46) thioalkyl;
(47) substituted thioalkyl;
(48) thioaryl;
(49) substituted thioaryl
(50) thioheteroaryl;
(51) substituted thioheteroaryl;
(52) thiocycloalkyl;
(53) substituted thiocycloalkyl;
(54) thioheterocyclic;
(55) substituted thioheterocyclic;
(56) R103;
(57) R104;
(58) guanidino;
(59) guanidinosulfone;
(60) halogen;
(61) nitro;
(62) R109;
(63) R110;
(64) R105;
(65) R106;
(66) cycloalkoxy;
(67) substituted cycloalkoxy;
(68) heteroaryloxy;
(69) substituted heteroaryloxy;
(70) heterocyclyloxy;
(71) substituted heterocyclyloxy;
(72) oxycarbonylamino;
(73) oxythiocarbonylamino;
(74) —S(O)2-alkyl wherein alkyl is R101;
(75) —S(O)2-substituted alkyl wherein substituted alkyl is R102;
(76) —S(O)2-cycloalkyl wherein cycloalkyl is R103;
(77) —S(O)2-substituted cycloalkyl wherein substituted cycloalkyl is R104;
(78) —S(O)2-alkenyl wherein alkenyl is R111;
(79) —S(O)2-substituted alkenyl wherein substituted alkenyl is R112;
(80) —S(O)2-aryl wherein aryl is R107;
(81) —S(O)2-substituted aryl wherein substituted aryl is R108;
(82) —S(O)2-heteroaryl wherein heteroaryl is R109;
(83) —S(O)2-substituted heteroaryl wherein substituted heteroaryl is R110;
(84) —S(O)2-heterocyclic wherein heterocyclic is R105;
(85) —S(O)2-substituted heterocyclic wherein substituted heterocyclic is R106;
(86) —OS(O)2-alkyl wherein alkyl is R101;
(87) —OS(O)2-substituted alkyl wherein substituted alkyl is R102;
(88) —OS(O)2-aryl wherein aryl is R107;
(89) —OS(O)2-substituted aryl wherein substituted aryl is R108;
(90) —OS(O)2-heteroaryl wherein heteroaryl is R109;
(91) —OS(O)2-substituted heteroaryl wherein substituted heteroaryl is R110;
(92) —OS(O)2-heterocyclic wherein heterocyclic is R105;
(93) —OS(O)2-substituted heterocyclic wherein substituted heterocyclic is R106;
(94) —OS(O)2—NRR where R is hydrogen or R101;
(95) —NRS(O)2-alkyl wherein alkyl is R101;
(96) —NRS(O)2-substituted alkyl wherein substituted alkyl is R102;
(97) —NRS(O)2-aryl wherein aryl is R107;
(98) —NRS(O)2-substituted aryl wherein substituted aryl is R108;
(99) —NRS(O)2-heteroaryl wherein heteroaryl is R109;
(100) —NRS(O)2-substituted heteroaryl wherein substituted heteroaryl is R110;
(101) —NRS(O)2-heterocyclic wherein heterocyclic is R105;
(102) —NRS(O)2-substituted heterocyclic wherein substituted heterocyclic is R106;
(103) —NRS(O)2—NR-alkyl wherein alkyl is R101;
(104) —NRS(O)2—NR-substituted alkyl wherein substituted alkyl is R102;
(105) —NRS(O)2—NR-aryl wherein aryl is R107;
(106) —NRS(O)2—NR-substituted aryl wherein substituted aryl is R108;
(107) —NRS(O)2—NR-heteroaryl wherein heteroaryl is R109;
(108) —NRS(O)2—NR-substituted heteroaryl wherein substituted heteroaryl is R110;
(109) —NRS(O)2—NR-heterocyclic wherein heterocyclic is R105;
(110) —NRS(O)2—NR-substituted heterocyclic wherein substituted heterocyclic is R106,
(111) mono- and di-alkylamino, wherein alkyl is R101;
(112) mono- and di-
(substituted alkyl)amino, wherein substituted alkyl is R102;
(113) mono- and di-arylamino wherein aryl is R107;
(114) mono- and di-substituted arylamino wherein substituted aryl is R108;
(115) mono- and di-heteroarylamino wherein heteroaryl is R109;
(116) mono- and di-substituted heteroarylamino wherein substituted heteroaryl is R110;
(117) mono- and di-heterocyclic amino wherein heterocyclic is R105;
(118) mono- and di-substituted heterocyclic amino wherein substituted heterocyclic is R106;
R300 is a member selected from
(i) —SO2-alkyl wherein alkyl is R101;
(ii) —SO2-substituted alkyl wherein substituted alkyl is R102;
(iii) —SO2-alkenyl wherein alkenyl is R111;
(iv) —SO2-substituted alkenyl wherein substituted alkenyl is R112;
(v) —SO2-cycloalkyl wherein cycloalkyl is R103;
(vi) —SO2-substituted cycloalkyl wherein substituted cycloalkyl is R104;
(vii) —SO2-aryl wherein aryl is R107;
(viii) —SO2-substituted aryl wherein substituted aryl is R108;
(ix) —SO2-heteroaryl wherein heteroaryl is R109;
(x) —SO2-substituted heteroaryl wherein substituted heteroaryl is R110;
(xi) —SO2-heterocyclic wherein heterocyclic is R105;
(xii) —SO2-substituted heterocyclic wherein substituted heterocyclic is R106;
and
(xiii) —SO2NRR;
alkoxy has the formula “alkyl-O—”, wherein alkyl is R101;
substituted alkoxy has the formula “substituted alkyl-O—”, wherein substituted alkyl is R102;
cycloalkoxy has the formula “—O-cycloalkyl”, wherein cycloalkyl is R103;
substituted cycloalkoxy has the formula “—O-substituted cycloalkyl”, wherein substituted cycloalkyl is R104;
alkenoxy has the formula “alkenyl-O—”, wherein alkenyl is R111;
substituted alkenoxy has the formula “substituted alkenyl-O—”, wherein substituted alkenyl is R112;
cycloalkenoxy has the formula “cycloalkenyl-O—”, wherein cycloalkenyl is R115;
substituted cycloalkenoxy has the formula “substituted cycloalkenyl-O—”, wherein substituted cycloalkenyl is R116;
aryloxy has the formula “aryl-O—”, wherein aryl is R107;
substituted aryloxy has the formula “substituted aryl-O—”, wherein substituted aryl is R108;
heteroaryloxy has the formula “—O-heteroary”, wherein heteroaryl is R109;
substituted heteroaryloxy has the formula “—O-substituted heteroaryl”, wherein substituted heteroaryl is R110;
heterocyclyloxy has the formula “—O-heterocyclic”, wherein heterocyclic is R105;
substituted heterocyclyloxy has the formula “—O-substituted heterocyclic”, wherein substituted heterocyclic is R106;
aryloxyaryl has the formula “aryl-O-aryl”, wherein each aryl is R107;
substituted aryloxyaryl has the formula “aryl-O-aryl”, wherein each aryl is R107, substituted on one or both aryl rings with from 1 to 3 substituents selected from the group consisting of
(1) R201;
(2) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(3) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(4) —SO2NRR;
acyl is Rc—C(O)—;
acylamino is selected from the group —C(O)NRcRc, wherein each Rc is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
thiocarbonylamino is selected from the group —C(S)NRcRc, wherein each Rc is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic R106;
acyloxy is selected from Rb—C(O)O—;
oxysulfonyl has the formula Rb—SO2O—;
amino has the formula —NH2;
substituted amino has the formula —NRdRd, where each Rd is independently selected from the group consisting of hydrogen, R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111, R112, R113, R114 and —SO2—Re, wherein Re is a member selected from R101, R102, R103, R104, R105, R106, R107, R109, R110, R111 and R112;
or the Rd groups can be joined together with the nitrogen atom to form a heterocyclic or a substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106,
provided that both Rd groups are not hydrogen;
amidino has the formula H2NC(═NH)—;
alkyl amidino is “alkylHNC(═NH)—”, wherein alkyl is R101;
thioamidino has the formula RSC(═NH)—;
aminoacyl has the formula —NRC(O)Rb;
aminosulfonyl having the formula —NRSO2Rb;
aminocarbonyloxy having the formula —NRC(O)O2Rb;
aminosulfonyloxy has the formula —NRSO2O2Rb;
oxycarbonylamino has the formula —OC(O)NH2, —OC(O)NRR or —OC(O)NRRb, wherein each R is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
oxythiocarbonylamino has the formula —OC(S)NH2, —OC(S)NRR or —OC(S)NRRb, wherein each R is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
aminocarbonylamino has the formula —NRfC(O)NRfRf or —NRfC(O)NRfRb, wherein each Rf is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
aminothiocarbonylamino has the formula —NRfC(S)NRfRf or —NRfSO2NRfRb, wherein each Rf is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
aminosulfonylamino has the formula —NRfSO2NRfRf or —NRfSO2NRfRb, wherein each Rf is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
oxysulfonylamino has the formula —OSO2NH2, —OSO2NRR or —OSO2NRRb, wherein each R is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
halogen is fluoro, chloro, bromo or iodo;
guanidino has the formula —NRfC(═NRf)NRfRf or —NRfC(═NRf)NRfRb;
guanidinosulfone has the formula —NRC(═NR)NRSO2—Rb;
thioaryl having the formula “—S-alky”, wherein alkyl is R101;
substituted thioalkyl has the formula “—S-substituted alkyl”, wherein substituted alkyl is R102;
thiocycloalkyl has the formula “—S-cycloalkyl”, wherein cycloalkyl is R103;
substituted thiocycloalkyl has the formula “—S-substituted cycloalkyl”, wherein substituted cycloalkyl is R104;
thioaryl has the formula “—S-aryl”, wherein aryl is R107;
substituted thioaryl has the formula “—S-substituted aryl”, wherein substituted aryl is R108;
thioheteroaryl has the formula “—S-heteroaryl”, wherein heteroaryl is R109;
substituted thioheteroaryl has the formula “—S-substituted heteroaryl”, wherein substituted heteroaryl is R110;
thioheterocyclic has the formula “—S-heterocyclic”, wherein heterocyclic is R105;
and
substituted thioheterocyclic has the formula “—S-substituted heterocyclic”, wherein substituted heterocyclic is R106;
wherein
each R is independently hydrogen or R101;
each Rb is a member independently selected from R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111, R112, R113 and R114;
each Rc is a member independently selected from H, R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111, R112, R113 and R114;
and
each Rf is independently hydrogen, R101 or a blocking group selected from tert butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl.

371 more elements

A compound having the formula:

or a pharmaceuticeutically acceptable salt thereof,
wherein
R5 is selected from the group consisting of R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111, R112, R115 and R116;
R6 is selected from the group consisting of R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R115 and R116;
R′ and R″ are independently selected from the group consisting of hydrogen and R101, or R′ and R″, together with the nitrogen to which they are bound, join to form a heterocyclic group, wherein heterocyclic is R105;
X is selected from the group consisting of hydroxyl, alkoxy and substituted alkoxy;
and
R9′ is selected from the group consisting of hydrogen, acylamino, aminoacyl, oxycarbonylamino, aminocarbonyloxy and R105,
wherein
R101 is alkyl of from 1 to 10 carbon atoms;
R102 is substituted alkyl of from 1 to 10 carbon atoms, having from 1 to 5 substituents selected from the group consisting of
(1) R200;
(2) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(3) amino groups blocked by blocking groups selected from the group consisting of tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(4) R300;
R103 is cycloalkyl of from 3 to 8 carbon atoms;
R104 is substituted cycloalkyl of from 3 to 8 carbon atoms, having from 1 to 5 substituents selected from the group consisting of
(1) R200;
(1) R200;
(2) oxo (═O);
(3) thioxo (═S);
(4) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(5) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(6) R300;
R105 is heterocyclic referring to a saturated or unsaturated group having from 1 to 10 carbon atoms and from 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen, and having a single ring or multiple fused rings, wherein in fused ring systems one or more of the rings can be aryl (R107) or heteroaryl (R109);
R106 is substituted heterocyclic of from 1 to 10 carbon atoms and from 1 to 4 heteroatoms, substituted with from 1 to 3 substituents selected from the group consisting of
(1) R200;
(2) oxo (═O);
(3) thioxo (═S);
(4) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(5) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
R107 is aryl, wherein aryl is an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring or multiple condensed rings, wherein the condensed rings may or may not be aromatic;
R108 is substituted aryl, wherein substituted aryl is aryl substituted with from 1 to 3 substituents selected from the group consisting of
(1) R201;
(2) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R105, R106, R107, R108, R109 and R110;
(3) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(4) —SO2NRR;
R109 is heteroaryl of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring or oxides thereof, having a single ring or multiple condensed rings;
R110 is substituted heteroaryl of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, substituted with from 1 to 3 substituents selected from the group consisting of
(1) R201;
(2) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(3) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(4) —SO2NRR;
R111 is alkenyl of from 2 to 10 carbon atoms and from 1 to 2 sites of alkenyl unsaturation;
R112 is substituted alkenyl, wherein substituted alkenyl is alkenyl substituted with from 1 to 5 substituents selected from the group consisting of
(1) R200;
(2) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(3) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(4) R300;
R113 is alkynyl of from 2 to 10 carbon atoms and from 1 to 2 sites of alkynyl unsaturation;
R114 is substituted alkynyl, wherein substituted alkynyl is alkynyl substituted with from 1 to 5 substituents selected from the group consisting of
(1) R200;
(2) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(3) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(4) R300;
R115 is cycloalkenyl, wherein cycloalkenyl is a cyclic alkenyl group of from 3 to 8 carbon atoms having single or multiple unsaturation, and which is not aromatic;
R116 is substituted cycloalkenyl of from 3 to 8 carbon atoms, having from 1 to 5 substituents selected from the group consisting of
(1) R200;
(2) oxo (═O);
(3) thioxo (═S);
and
(4) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(5) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(6) R300;
wherein
R200 is a member selected from
(1) alkoxy;
(2) substituted alkoxy;
(3) acyl;
(4) acylamino;
(5) thiocarbonylamino;
(6) acyloxy;
(7) amino;
(8) amidino;
(9) alkylamidino wherein alkyl is R101;
(10) thioamidino;
(11) aminoacyl;
(12) aminocarbonylamino;
(13) aminothiocarbonylamino;
(14) aminocarbonyloxy;
(15) R107;
(16) R108;
(17) aryloxy;
(18) substituted aryloxy;
(19) aryloxyaryl;
(20) substituted aryloxyaryl;
(21) halogen;
(22) hydroxyl;
(23) cyano;
(24) nitro;
(25) carboxyl;
(26) carboxylalkyl wherein alkyl is R101;
(27) carboxyl-substituted alkyl wherein substituted alkyl is R102;
(28) carboxyl-cycloalkyl wherein cycloalkyl is R103;
(29) carboxyl-substituted cycloalkyl wherein substituted cycloalkyl is R104;
(30) carboxylaryl wherein aryl is R107;
(31) carboxyl-substituted aryl wherein substituted aryl is R108;
(32) carboxylheteroaryl wherein heteroaryl is R109;
(33) carboxyl-substituted heteroaryl wherein substituted heteroaryl is R110;
(34) carboxylheterocyclic wherein heterocyclic is R105;
(35) carboxyl-substituted heterocyclic wherein substituted heterocyclic is R106;
(36) R103;
(36) R104;
(38) guanidino;
(39) guanidinosulfone;
(40) thiol having the formula —SH;
(41) thioaryl;
(42) substituted thioalkyl;
(43) thioaryl;
(44) substituted thioaryl;
(45) thiocycloalkyl;
(46) substituted thiocycloalkyl;
(47) thioheteroaryl;
(48) substituted thioheteroaryl;
(49) thioheterocyclic;
(50) substituted thioheterocyclic;
(51) R109;
(52) R110;
(53) R105;
(54) R106;
(55) cycloalkoxy;
(56) substituted cycloalkoxy;
(57) heteroaryloxy;
(58) substituted heteroaryloxy;
(59) heterocyclyloxy;
(60) substituted heterocyclyloxy;
(61) oxycarbonylamino;
(62) oxythiocarbonylamino;
(63) —OS(O)2-alkyl, wherein alkyl is R101;
(64) —OS(O)2-substituted alkyl wherein substituted alkyl is R102;
(65) —OS(O)2-aryl, wherein aryl is R107;
(66) —OS(O)2-substituted aryl wherein substituted aryl is R108;
(67) —OS(O)2-heteroaryl wherein heteroaryl is R109;
(68) —OS(O)2-substituted heteroaryl wherein substituted heteroaryl is R110;
(69) —OS(O)2-heterocyclic wherein heterocyclic is R105;
(70) —OS(O)2-substituted heterocyclic wherein substituted heterocyclic is R106;
(71) —NRR where R is hydrogen or R101;
(72) —NRS(O)2-alkyl, wherein alkyl is R101;
(73) —NRS(O)2-substituted alkyl wherein substituted alkyl is R102;
(74) —NRS(O)2-aryl, wherein aryl is R107;
(75) —NRS(O)2-substituted aryl wherein substituted aryl is R108;
(76) —NRS(O)2-heteroaryl wherein heteroaryl is R109;
(77) —NRS(O)2-substituted heteroaryl wherein substituted heteroaryl is R110;
(78) —NRS(O)2-heterocyclic wherein heterocyclic is R105;
(79) —NRS(O)2-substituted heterocyclic wherein substituted heterocyclic is R106;
(80) —NRS(O)2—NR-alkyl, wherein alkyl is R101;
(81) —NRS(O)2—NR-substituted alkyl wherein substituted alkyl is R102;
(82) —NRS(O)2—NR-aryl, wherein aryl is R107;
(83) —NRS(O)2—NR-substituted aryl wherein substituted aryl is R108;
(84) —NRS(O)2—NR-heteroaryl wherein heteroaryl is R109;
(85) —NRS(O)2—NR-substituted heteroaryl wherein substituted heteroaryl is R110;
(86) —NRS(O)2—NR-heterocyclic wherein heterocyclic is R105;
(87) —NRS(O)2—NR-substituted heterocyclic wherein substituted heterocyclic is R106,
(88) mono- and di-alkylamino, wherein alkyl is R101;
(89) mono- and di-(substituted alkyl)amino, wherein substituted alkyl is R102;
(90) mono- and di-arylamino wherein aryl is R107;
(91) mono- and di-substituted arylamino wherein substituted aryl is R108;
(92) mono- and di-heteroarylamino wherein heteroaryl is R109;
(93) mono- and di-substituted heteroarylamino wherein substituted heteroaryl is R110;
(94) mono- and di-heterocyclic amino wherein heterocyclic is R105;
and
(95) mono- and di-substituted heterocyclic amino wherein substituted heterocyclic is R106;
R201 is a member selected from
(1) hydroxyl;
(2) acyl;
(3) acylamino;
(4) thiocarbonylamino;
(5) acyloxy;
(6) R101;
(7) R102;
(8) alkoxy;
(9) substituted alkoxy;
(10) R111;
(11) R112;
(12) R113;
(13) R114;
(14) amidino;
(15) alkylamidino, wherein alkyl is R101;
(16) thioamidino;
(17) amino;
(18) aminoacyl;
(19) aminocarbonyloxy;
(20) aminocarbonylamino;
(21) aminothiocarbonylamino;
(22) R107;
(23) R108;
(24) aryloxy;
(25) substituted aryloxy;
(26) cycloalkoxy;
(27) substituted cycloalkoxy;
(28) heteroaryloxy;
(29) substituted heteroaryloxy;
(30) heterocyclyloxy;
(31) substituted heterocyclyloxy;
(32) carboxyl;
(33) carboxylalkyl wherein alkyl is R101;
(34) carboxyl-substituted alkyl wherein substituted alkyl is R102;
(35) carboxyl-cycloalkyl wherein cycloalkyl is R103;
(36) carboxyl-substituted cycloalkyl wherein substituted cycloalkyl is R104;
(37) carboxylaryl wherein aryl is R107;
(38) carboxyl-substituted aryl wherein substituted aryl is R108;
(39) carboxylheteroaryl wherein heteroaryl is R109;
(40) carboxyl-substituted heteroaryl wherein substituted heteroaryl is R110;
(41) carboxylheterocyclic wherein heterocyclic is R105;
(42) carboxyl-substituted heterocyclic wherein substituted heterocyclic is R106;
(43) carboxylamido;
(44) cyano;
(45) thiol having the formula —SH;
(46) thioalkyl;
(47) substituted thioalkyl;
(48) thioaryl;
(49) substituted thioaryl
(50) thioheteroaryl;
(51) substituted thioheteroaryl;
(52) thiocycloalkyl;
(53) substituted thiocycloalkyl;
(54) thioheterocyclic;
(55) substituted thioheterocyclic;
(56) R103;
(57) R104;
(58) guanidino;
(59) guanidinosulfone;
(60) halogen;
(61) nitro;
(62) R109;
(63) R110;
(64) R105;
(65) R106;
(66) cycloalkoxy;
(67) substituted cycloalkoxy;
(68) heteroaryloxy;
(69) substituted heteroaryloxy;
(70) heterocyclyloxy;
(71) substituted heterocyclyloxy;
(72) oxycarbonylamino;
(73) oxythiocarbonylamino;
(74) —S(O)2-alkyl wherein alkyl is R101;
(75) —S(O)2-substituted alkyl wherein substituted alkyl is R102;
(76) —S(O)2-cycloalkyl wherein cycloalkyl is R103;
(77) —S(O)2-substituted cycloalkyl wherein substituted cycloalkyl is R104;
(78) —S(O)2-alkenyl wherein alkenyl is R111;
(79) —S(O)2-substituted alkenyl wherein substituted alkenyl is R102;
(80) —S(O)2-aryl wherein aryl is R107;
(81) —S(O)2-substituted aryl wherein substituted aryl is R108;
(82) —S(O)2-heteroaryl wherein heteroaryl is R109;
(83) —S(O)2-substituted heteroaryl wherein substituted heteroaryl is R110;
(84) —S(O)2-heterocyclic wherein heterocyclic is R105;
(85) —S(O)2-substituted heterocyclic wherein substituted heterocyclic is R106;
(86) —OS(O)2-alkyl wherein alkyl is R101;
(87) —OS(O)2-substituted alkyl wherein substituted alkyl is R102;
(88) —OS(O)2-aryl wherein aryl is R107;
(89) —OS(O)2-substituted aryl wherein substituted aryl is R108;
(90) —OS(O)2-heteroaryl wherein heteroaryl is R109;
(91) —OS(O)2-substituted heteroaryl wherein substituted heteroaryl is R110;
(92) —OS(O)2-heterocyclic wherein heterocyclic is R105;
(93) —OS(O)2-substituted heterocyclic wherein substituted heterocyclic is R106;
(94) —OS(O)2—NRR where R is hydrogen or R101;
(95) —NRS(O)2-alkyl wherein alkyl is R101;
(96) —NRS(O)2-substituted alkyl wherein substituted alkyl is R102;
(97) —NRS(O)2-aryl wherein aryl is R107;
(98) —NRS(O)2-substituted aryl wherein substituted aryl is R108;
(99) —NRS(O)2-heteroaryl wherein heteroaryl is R109;
(100) —NRS(O)2-substituted heteroaryl wherein substituted heteroaryl is R110;
(101) —NRS(O)2-heterocyclic wherein heterocyclic is R105;
(102) —NRS(O)2-substituted heterocyclic wherein substituted heterocyclic is R106;
(103) —NRS(O)2—NR-alkyl wherein alkyl is R101;
(104) —NRS(O)2—NR-substituted alkyl wherein substituted alkyl is R102;
(105) —NRS(O)2—NR-aryl wherein aryl is R107;
(106) —NRS(O)2—NR-substituted aryl wherein substituted aryl is R108;
(107) —NRS(O)2—NR-heteroaryl wherein heteroaryl is R109;
(108) —NRS(O)2—NR-substituted heteroaryl wherein substituted heteroaryl is R110;
(109) —NRS(O)2—NR-heterocyclic wherein heterocyclic is R105;
(110) —NRS(O)2—NR-substituted heterocyclic wherein substituted heterocyclic is R106,
(111) mono- and di-alkylamino, wherein alkyl is R101;
(112) mono- and di-(substituted alkyl)amino, wherein substituted alkyl is R102;
(113) mono- and di-arylamino wherein aryl is R107;
(114) mono- and di-substituted arylamino wherein substituted aryl is R108;
(115) mono- and di-heteroarylamino wherein heteroaryl is R109;
(116) mono- and di-substituted heteroarylamino wherein substituted heteroaryl is R110;
(117) mono- and di-heterocyclic amino wherein heterocyclic is R105;
(118) mono- and di-substituted heterocyclic amino wherein substituted heterocyclic is R106;
R300 is a member selected from
(i) —SO2-alkyl wherein alkyl is R101;
(ii) —SO2-substituted alkyl wherein substituted alkyl is R102;
(iii) —SO2-alkenyl wherein alkenyl is R111;
(iv) —SO2-substituted alkenyl wherein substituted alkenyl is R112;
(v) —SO2-cycloalkyl wherein cycloalkyl is R103;
(vi) —SO2-substituted cycloalkyl wherein substituted cycloalkyl is R104;
(vii) —SO2-aryl wherein aryl is R107;
(viii) —SO2-substituted aryl wherein substituted aryl is R108;
(ix) —SO2-heteroaryl wherein heteroaryl is R109;
(x) —SO2-substituted heteroaryl wherein substituted heteroaryl is R110;
(xi) —SO2-heterocyclic wherein heterocyclic is R105;
(xii) —SO2-substituted heterocyclic wherein substituted heterocyclic is R106;
and
(xiii) —SO2NRR;
alkoxy has the formula “alkyl-O—”, wherein alkyl is R101;
substituted alkoxy has the formula “substituted alkyl-O—”, wherein substituted alkyl is R102;
cycloalkoxy has the formula “—O-cycloalkyl”, wherein cycloalkyl is R103;
substituted cycloalkoxy has the formula “—O-substituted cycloalkyl”, wherein substituted cycloalkyl is R104;
alkenoxy has the formula “alkenyl-O—”, wherein alkenyl is R111;
substituted alkenoxy has the formula “substituted alkenyl-O—”, wherein substituted alkenyl is R112;
cycloalkenoxy has the formula “cycloalkenyl-O—”, wherein cycloalkenyl is R115;
substituted cycloalkenoxy has the formula “substituted cycloalkenyl-O—”, wherein substituted cycloalkenyl is R116;
aryloxy has the formula “aryl-O—”, wherein aryl is R107;
substituted aryloxy has the formula “substituted aryl-O—”, wherein substituted aryl is R108;
heteroaryloxy has the formula “—O-heteroary”, wherein heteroaryl is R109;
substituted heteroaryloxy has the formula “—O-substituted heteroaryl”, wherein substituted heteroaryl is R110;
heterocyclyloxy has the formula “—O-heterocyclic”, wherein heterocyclic is R105;
substituted heterocyclyloxy has the formula “—O-substituted heterocyclic”, wherein substituted heterocyclic is R106;
aryloxyaryl has the formula “aryl-O-aryl”, wherein each aryl is R107;
substituted aryloxyaryl has the formula “aryl-O-aryl”, wherein each aryl is R107, substituted on one or both aryl rings with from 1 to 3 substituents selected from the group consisting of
(1) R201;
(2) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(3) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(4) —SO2NRR;
acyl is Rc-C(O)—;
acyl is Rc—C(O)—;
acylamino is selected from the group —C(O)NRcRc, wherein each Rc is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
thiocarbonylamino is selected from the group —C(S)NRcRc, wherein each Rc is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic R106;
acyloxy is selected from Rb—C(O)O—;
oxysulfonyl has the formula Rb—SO2O—;
amino has the formula —NH2;
substituted amino has the formula —NRdRd, where each Rd is independently selected from the group consisting of hydrogen, R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111, R112, R113, R114 and —SO2—Re, wherein Re is a member selected from R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111 and R112;
or the Rd groups can be joined together with the nitrogen atom to form a heterocyclic or a substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106,
provided that both Rd groups are not hydrogen;
amidino has the formula H2NC(═NH)—;
alkyl amidino is “alkylHNC(═NH)—”, wherein alkyl is R101;
thioamidino has the formula RSC(═NH)—;
aminoacyl has the formula —NRC(O)Rb;
aminosulfonyl having the formula —NRSO2Rb;
aminocarbonyloxy having the formula —NRC(O)O2Rb;
aminosulfonyloxy has the formula —NRSO2O2Rb;
oxycarbonylamino has the formula —OC(O)NH2, —OC(O)NRR or —OC(O)NRRb, wherein each R is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
oxythiocarbonylamino has the formula —OC(S)NH2, —OC(S)NRR or —OC(S)NRRb, wherein each R is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
aminocarbonylamino has the formula —NRfC(O)NRfRf or —NRfC(O)NRfRb, wherein each Rf is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
aminothiocarbonylamino has the formula —NRfC(S)NRfRf or —NRfSO2NRfRb, wherein each Rf is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
aminosulfonylamino has the formula —NRfSO2NRfRf or —NRfSOb 2NRRb, wherein each Rf is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
oxysulfonylamino has the formula —OSO2NH2, —OSO2NRR or —OSO2NRRb, wherein each R is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
halogen is fluoro, chloro, bromo or iodo;
guanidino has the formula —NRfC(═NRf)NRfRf or —NRfC(═NRf)NRfRb;
guanidinosulfone has the formula —NRC(═NR)NRSO2Rb;
thioaryl having the formula “—S-alky”, wherein alkyl is R101;
substituted thioalkyl has the formula “—S-substituted alkyl”, wherein substituted alkyl is R102;
thiocycloalkyl has the formula “—S-cycloalkyl”, wherein cycloalkyl is R103;
substituted thiocycloalkyl has the formula “—S-substituted cycloalkyl”, wherein substituted cycloalkyl is R104;
thioaryl has the formula “—S-aryl”, wherein aryl is R107;
substituted thioaryl has the formula “—S-substituted aryl”, wherein substituted aryl is R108;
thioheteroaryl has the formula “—S-heteroaryl”, wherein heteroaryl is R109;
substituted thioheteroaryl has the formula “—S-substituted heteroaryl”, wherein substituted heteroaryl is R110;
thioheterocyclic has the formula “—S-heterocyclic”, wherein heterocyclic is R105;
and
substituted thioheterocyclic has the formula “—S-substituted heterocyclic”, wherein substituted heterocyclic is R106;
wherein
each R is independently hydrogen or R101;
each Rb is a member independently selected from R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111, R112, R113 and R114;
each Rc is a member independently selected from R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111, R112, R113 and R114;
and
each Rf is independently hydrogen, R101 or a blocking group selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl.

365 more elements

A method for treating rheumatoid arthritis in a patient, which method comprises administering to the patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula IIa:

or a pharmaceutically acceptable salt thereof,
wherein
ring A forms a pyrimidine ring, optionally substituted with 1 or 2 substituents selected from the group consisting of R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, alkoxy, substituted alkoxy, amino, substituted amino and halogen,
R3is —(CH2)x—Ar—R9, wherein
Ar is R107 or R109;
x is an integer from 0 to 4;
and
R9 is selected from the group consisting of acyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, oxycarbonylamino, thioamidino, thiocarbonylamino, aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylamino and oxysulfonyl;
R3′ is hydrogen;
Q is —NR4—, wherein R4 is hydrogen or R101;
R5 is selected from the group consisting of R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111, R112, R115 and R116;
R6 is selected from the group consisting of hydrogen, R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R115 and R116;
and
X is selected from the group consisting of hydroxyl, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, cycloalkoxy, substituted cycloalkoxy, cycloalkenoxy, substituted cycloalkenoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy and —NR″R″, wherein each R″ is independently selected from the group consisting of hydrogen, R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111 and R112,
wherein
R101 is alkyl of from 1 to 10 carbon atoms;
R102 is substituted alkyl of from 1 to 10 carbon atoms, having from 1 to 5 substituents selected from the group consisting of
(1) R200;
(2) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(3) amino groups blocked by blocking groups selected from the group consisting of tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(4) R300;
R103 is cycloalkyl of from 3 to 8 carbon atoms;
R104 is substituted cycloalkyl of from 3 to 8 carbon atoms, having from 1 to 5 substituents selected from the group consisting of
(1) 200;
(2) oxo (═O);
(3) thioxo (═S);
(4) unsymmetric di-substituted amities having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105and R106;
(5) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(6) R300;
R105 is heterocyclic referring to a saturated or unsaturated group having from 1 to 10 carbon atoms and from 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen, and having a single ring or multiple fused rings, wherein in fused ring systems one or more of the rings can be aryl (R107) or heteroaryl (R109);
R106 is substituted heterocyclic of from 1 to 10 carbon atoms and from 1 to 4 heteroatoms, substituted with from 1 to 3 substituents selected from the group consisting of
(1) R200;
(2) oxo (═O);
(3) thioxo (═S);
(4) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(5) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(6) R300;
R107 is aryl, wherein aryl is an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring or multiple condensed rings, wherein the condensed rings may or may not be aromatic;
R108 is substituted aryl, wherein substituted aryl is aryl substituted with from 1 to 3 substituents selected from the group consisting of
(1) R201;
(2) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R105, R106, R107, R108, R109 and R110;
(3) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(4) —SO2NRR;
R109 is heteroaryl of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring or oxides thereof, having a single ring or multiple condensed rings;
R110 is substituted heteroaryl of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, substituted with from 1 to 3 substituents selected from the group consisting of
(1) R201;
(2) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(3) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(4) —SO2NRR;
R111 is alkenyl of from 2 to 10 carbon atoms and from 1 to 2 sites of alkenyl unsaturation;
R112 is substituted alkenyl, wherein substituted alkenyl is alkenyl substituted with from 1 to 5 substituents selected from the group consisting of
(1) R200;
(2) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(3) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(4) R300;
R113 is alkynyl of from 2 to 10 carbon atoms and from 1 to 2 sites of alkynyl unsaturation;
R114 is substituted alkynyl, wherein substituted alkynyl is alkynyl substituted with from 1 to 5 substituents selected from the group consisting of
(1) R200;
(2) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(3) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(4) R300;
R115 is cycloalkenyl, wherein cycloalkenyl is a cyclic alkenyl group of from 3 to 8 carbon atoms having single or multiple unsaturation, and which is not aromatic;
R116 is substituted cycloalkenyl of from 3 to 8 carbon atoms, having from 1 to 5 substituents selected from the group consisting of
(1) R200;
(2) oxo (═O);
(3) thioxo (═S);
and
(4) unsymmetric di-substituted amities having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(5) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(6) R300;
wherein
R200 is a member selected from
(1) alkoxy;
(2) substituted alkoxy;
(3) acyl;
(4) acylamino;
(5) thiocarbonylamino;
(6) acyloxy;
(7) amino;
(8) amidino;
(9) alkylamidino wherein alkyl is R101;
(10) thioamidino;
(11) aminoacyl;
(12) aminocarbonylamino;
(13) aminothiocarbonylamino;
(14) aminocarbonyloxy;
(15) R107;
(16) R108;
(17) aryloxy;
(18) substituted aryloxy;
(19) aryloxyaryl;
(20) substituted aryloxyaryl;
(21) halogen;
(22) hydroxyl;
(23) cyano;
(24) nitro;
(25) carboxyl;
(26) carboxylalkyl wherein alkyl is R101;
(27) carboxyl-substituted alkyl wherein substituted alkyl is R102;
(28) carboxyl-cycloalkyl wherein cycloalkyl is R103;
(29) carboxyl-substituted cycloalkyl wherein substituted cycloalkyl is R104;
(30) carboxylaryl wherein aryl is R107;
(31) carboxyl-substituted aryl wherein substituted aryl is R108;
(32) carboxylheteroaryl wherein heteroaryl is R109;
(33) carboxyl-substituted heteroaryl wherein substituted heteroaryl is R110;
(34) carboxylheterocyclic wherein heterocyclic is R105;
(35) carboxyl-substituted heterocyclic wherein substituted heterocyclic is R106;
(36) R103;
(37) R104;
(38) guanidino;
(39) guanidinosulfone;
(40) thiol having the formula —SH;
(41) thioaryl;
(42) substituted thioalkyl;
(43) thioaryl;
(44) substituted thioaryl;
(45) thiocycloalkyl;
(46) substituted thiocycloalkyl;
(47) thioheteroaryl;
(48) substituted thioheteroaryl;
(49) thioheterocyclic;
(50) substituted thioheterocyclic;
(51) R109;
(52) R110;
(53) R105;
(54) R106;
(55) cycloalkoxy;
(56) substituted cycloalkoxy;
(57) heteroaryloxy;
(58) substituted heteroaryloxy;
(59) heterocyclyloxy;
(60) substituted heterocyclyloxy;
(61) oxycarbonylamino;
(62) oxythiocarbonylamino;
(63) —OS(O)2-alkyl, wherein alkyl is R101;
(64) —OS(O)2-substituted alkyl wherein substituted alkyl is R102;
(65) —OS(O)2-aryl, wherein aryl is R107;
(66) —OS(O)2-substituted aryl wherein substituted aryl is R108;
(67) —OS(O)2-heteroaryl wherein heteroaryl is R109;
(68) —OS(O)2-substituted heteroaryl wherein substituted heteroaryl is R110;
(69) —OS(O)2-heterocyclic wherein heterocyclic is R105;
(70) —OS(O)2-substituted heterocyclic wherein substituted heterocyclic is R106;
(71) —OSO2—NRR where R is hydrogen or R101;
(72) —NRS(O)2-alkyl, wherein alkyl is R101;
(73) —NRS(O)2-substituted alkyl wherein substituted alkyl is R102;
(74) —NRS(O)2-aryl, wherein aryl is R107;
(75) —NRS(O)2-substituted aryl wherein substituted aryl is R108;
(76) —NRS(O)2-heteroaryl wherein heteroaryl is R109;
(77) —NRS(O)2-substituted heteroaryl wherein substituted heteroaryl is R110;
(78) —NRS(O)2-heterocyclic wherein heterocyclic is R105;
(79) —NRS(O)2-substituted heterocyclic wherein substituted heterocyclic is R106;
(80) —NRS(O)2—NR-alkyl, wherein alkyl is R101;
(81) —NRS(O)2—NR-substituted alkyl wherein substituted alkyl is R102;
(82) —NRS(O)2—NR-aryl, wherein aryl is R107;
(83) —NRS(O)2—NR-substituted aryl wherein substituted aryl is R108;
(84) —NRS(O)2—NR-heteroaryl wherein heteroaryl is R109;
(85) —NRS(O)2—NR-substituted heteroaryl wherein substituted heteroaryl is R110;
(86) —NRS(O)2—NR-heterocyclic wherein heterocyclic is R105;
(87) —NRS(O)2—NR-substituted heterocyclic wherein substituted heterocyclic is R106,
(88) mono- and di-alkylamino, wherein alkyl is R101;
(89) mono- and di-(substituted alkyl)amino, wherein substituted alkyl is R102;
(90) mono- and di-arylamino wherein aryl is R107;
(91) mono- and di-substituted arylamino wherein substituted aryl is R108;
(92) mono- and di-heteroarylamino wherein heteroaryl is R109;
(93) mono- and di-substituted heteroarylamino wherein substituted heteroaryl is R110;
(94) mono- and di-heterocyclic amino wherein heterocyclic is R105;
and (95) mono- and di-substituted heterocyclic amino wherein substituted heterocyclic is R106;
R201 is a member selected from
(1) hydroxyl;
(2) acyl;
(3) acylamino;
(4) thiocarbonylamino;
(5) acyloxy;
(6) R101;
(7) R102;
(8) alkoxy;
(9) substituted alkoxy;
(10) R111;
(11) R112;
(12) R113;
(13) R114;
(14) amidino;
(15) alkylamidino, wherein alkyl is R101;
(16) thioamidino;
(17) amino;
(18) aminoacyl;
(19) aminocarbonyloxy;
(20) aminocarbonylamino;
(21) aminothiocarbonylamino;
(22) R107;
(23) R108;
(24) aryloxy;
(25) substituted aryloxy;
(26) cycloalkoxy;
(27) substituted cycloalkoxy;
(28) heteroaryloxy;
(29) substituted heteroaryloxy;
(30) heterocyclyloxy;
(31) substituted heterocyclyloxy;
(32) carboxyl;
(33) carboxylalkyl wherein alkyl is R101;
(34) carboxyl-substituted alkyl wherein substituted alkyl is R102;
(35) carboxyl-cycloalkyl wherein cycloalkyl is R103;
(36) carboxyl-substituted cycloalkyl wherein substituted cycloalkyl is R104;
(37) carboxylaryl wherein aryl is R107;
(38) carboxyl-substituted aryl wherein substituted aryl is R108;
(39) carboxylheteroaryl wherein heteroaryl is R109;
(40) carboxyl-substituted heteroaryl wherein substituted heteroaryl is R110;
(41) carboxylheterocyclic wherein heterocyclic is R105;
(42) carboxyl-substituted heterocyclic wherein substituted heterocyclic is R106;
(43) carboxylamido;
(44) cyano;
(45) thiol having the formula —SH;
(46) thioalkyl;
(47) substituted thioalkyl;
(48) thioaryl;
(49) substituted thioaryl
(50) thioheteroaryl;
(51) substituted thioheteroaryl;
(52) thiocycloalkyl;
(53) substituted thiocycloalkyl;
(54) thioheterocyclic;
(55) substituted thioheterocyclic;
(56) R103;
(57) R104;
(58) guanidino;
(59) guanidinosulfone;
(60) halogen;
(61) nitro;
(62) R109;
(63) R110;
(64) R105;
(65) R106;
(66) cycloalkoxy;
(67) substituted cycloalkoxy;
(68) heteroaryloxy;
(69) substituted heteroaryloxy;
(70) heterocyclyloxy;
(71) substituted heterocyclyloxy;
(72) oxycarbonylamino;
(73) oxythiocarbonylamino;
(74) —S(O)2-alkyl wherein alkyl is R101;
(75) —S(O)2-substituted alkyl wherein substituted alkyl is R102;
(76) —S(O)2-cycloalkyl wherein cycloalkyl is R103;
(77) —S(O)2-substituted cycloalkyl wherein substituted cycloalkyl is R104;
(78) —S(O)2-alkenyl wherein alkenyl is R111;
(79) —S(O)2-substituted alkenyl wherein substituted alkenyl is R112;
(80) —S(O)2-aryl wherein aryl is R107;
(81) —S(O)2-substituted aryl wherein substituted aryl is R108;
(82) —S(O)2-heteroaryl wherein heteroaryl is R109;
(83) —S(O)2-substituted heteroaryl wherein substituted heteroaryl is R110;
(84) —S(O)2-heterocyclic wherein heterocyclic is R105;
(85) —S(O)2-substituted heterocyclic wherein substituted heterocyclic is R106;
(86) —OS(O)2-alkyl wherein alkyl is R101;
(87) —OS(O)2-substituted alkyl wherein substituted alkyl is R102;
(88) —OS(O)2-aryl wherein aryl is R107;
(89) —OS(O)2-substituted aryl wherein substituted aryl is R108;
(90) —OS(O)2-heteroaryl wherein heteroaryl is R109;
(91) —OS(O)2-substituted heteroaryl wherein substituted heteroaryl is R110;
(92) —OS(O)2-heterocyclic wherein heterocyclic is R105;
(93) —OS(O)2-substituted heterocyclic wherein substituted heterocyclic is R106;
(94) —OSO2—NRR where R is hydrogen or R101;
(95) —NRS(O)2-alkyl wherein alkyl is R101;
(96) —NRS(O)2-substituted alkyl wherein substituted alkyl is R102;
(97) —NRS(O)2-aryl wherein aryl is R107;
(98) —NRS(O)2-substituted aryl wherein substituted aryl is R108;
(99) —NRS(O)2-heteroaryl wherein heteroaryl is R109;
(100) —NRS(O)2-substituted heteroaryl wherein substituted heteroaryl is R110;
(101) —NRS(O)2-heterocyclic wherein heterocyclic is R105;
(102) —NRS(O)2-substituted heterocyclic wherein substituted heterocyclic is R106;
(103) —NRS(O)2—NR-alkyl wherein alkyl is R101;
(104) —NRS(O)2—NR-substituted alkyl wherein substituted alkyl is R102;
(105) —NRS(O)2—NR-aryl wherein aryl is R107;
(106) —NRS(O)2—NR-substituted aryl wherein substituted aryl is R108;
(107) —NRS(O)2—NR-heteroaryl wherein heteroaryl is R109;
(108) —NRS(O)2—NR-substituted heteroaryl wherein substituted heteroaryl is R110;
(109) —NRS(O)2—NR-heterocyclic wherein heterocyclic is R105;
(110) —NRS(O)2—NR-substituted heterocyclic wherein substituted heterocyclic is R106,
(111) mono- and di-alkylamino, wherein alkyl is R101;
(112) mono- and di-(substituted alkyl)amino, wherein substituted alkyl is R102;
(113) mono- and di-arylamino wherein aryl is R107;
(114) mono- and di-substituted arylamino wherein substituted aryl is R108;
(115) mono- and di-heteroarylamino wherein heteroaryl is R109;
(116) mono- and di-substituted heteroarylamino wherein substituted heteroaryl is R110;
(117) mono- and di-heterocyclic amino wherein heterocyclic is R105;
(118) mono- and di-substituted heterocyclic amino wherein substituted heterocyclic is R106;
R300 is a member selected from
(i) —SO2-alkyl wherein alkyl is R101;
(ii) —SO2-substituted alkyl wherein substituted alkyl is R102;
(iii) —SO2-alkenyl wherein alkenyl is R111;
(iv) —SO2-substituted alkenyl wherein substituted alkenyl is R112;
(v) —SO2-cycloalkyl wherein cycloalkyl is R103;
(vi) —SO2-substituted cycloalkyl wherein substituted cycloalkyl is R104;
(vii) —SO2-aryl wherein aryl is R107;
(viii) —SO2-substituted aryl wherein substituted aryl is R108;
(ix) —SO2-heteroaryl wherein heteroaryl is R109;
(x) —SO2-substituted heteroaryl wherein substituted heteroaryl is R110;
(xi) —SO2-heterocyclic wherein heterocyclic is R105;
(xii) —SO2-substituted heterocyclic wherein substituted heterocyclic is R106;
and
(xiii) —SO2NRR;
alkoxy has the formula “alkyl-O—”, wherein alkyl is R101;
substituted alkoxy has the formula “substituted alkyl-O—”, wherein substituted alkyl is R102;
cycloalkoxy has the formula “—O-cycloalkyl”, wherein cycloalkyl is R103;
substituted cycloalkoxy has the formula “—O-substituted cycloalkyl”, wherein substituted cycloalkyl is R104;
alkenoxy has the formula “alkenyl-O—”, wherein alkenyl is R111;
substituted alkenoxy has the formula “substituted alkenyl-O—”, wherein substituted alkenyl is R112;
cycloalkenoxy has the formula “cycloalkenyl-O—”, wherein cycloalkenyl is R115;
substituted cycloalkenoxy has the formula “substituted cycloalkenyl-O—”, wherein substituted cycloalkenyl is R116;
aryloxy has the formula “aryl-O—”, wherein aryl is R107;
substituted aryloxy has the formula “substituted aryl-O—”, wherein substituted aryl is R108;
heteroaryloxy has the formula “—O-heteroary”, wherein heteroaryl is R109;
substituted heteroaryloxy has the formula “—O-substituted heteroaryl”, wherein substituted heteroaryl is R110;
heterocyclyloxy has the formula “—O-heterocyclic”, wherein heterocyclic is R105;
substituted heterocyclyloxy has the formula “—O-substituted heterocyclic”, wherein substituted heterocyclic is R106;
aryloxyaryl has the formula “aryl-O-aryl”, wherein each aryl is R107;
substituted aryloxyaryl has the formula “aryl-O-aryl”, wherein each aryl is R107, substituted on one or both aryl rings with from 1 to 3 substituents selected from the group consisting of
(1) R201;
(2) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(3) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(4) —SO2NRR;
acyl is Rc—C(O)—;
acylamino is selected from the group —C(O)NRcRc, wherein each Rc is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
thiocarbonylamino is selected from the group —C(S)NRcRc, wherein each Rc is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic R106;
acyloxy is selected from Rb—C(O)O—;
oxysulfonyl has the formula Rb—SO2O—;
amino has the formula —NH2;
substituted amino has the formula —NRdRd, where each Rd is independently selected from the group consisting of hydrogen, R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111, R112, R113, R114 and —SO2—Re, wherein Re is a member selected from R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111 and R112;
or the Rd groups can be joined together with the nitrogen atom to form a heterocyclic or a substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106,
provided that both Rd groups are not hydrogen;
amidino has the formula H2NC(═NH)—;
alkyl amidino is “alkylHNC(═NH)—”, wherein alkyl is R101;
thioamidino has the formula RSC(═NH)—;
aminoacyl has the formula —NRC(O)Rb;
aminosulfonyl having the formula —NRSO2Rb;
aminocarbonyloxy having the formula —NRC(O)O2Rb;
aminosulfonyloxy has the formula —NRSO2O—Rb;
oxycarbonylamino has the formula —OC(O)NH2, —OC(O)NRR or —OC(O)NRRb, wherein each R is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
oxythiocarbonylamino has the formula —OC(S)NH2, —OC(S)NRR or —OC(S)NRRb, wherein each R is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
aminocarbonylamino has the formula —NRfC(O)NRfRf or —NRfC(O)NRfRb, wherein each Rf is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
aminothiocarbonylamino has the formula —NRfC(S)NRfRf or —NRfC(S)NRfRb, wherein each Rf is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
aminosulfonylamino has the formula —NRfSO2NRfRf or —NRfSO2NRfRb, wherein each Rf is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
oxysulfonylamino has the formula —OSO2NH2, —OSO2NRR or —OSO2NRRb, wherein each R is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
halogen is fluoro, chloro, bromo or iodo;
guanidino has the formula —NRfC(═NRf)NRfRf or —NRfC(═NRf)NRf Rb;
guanidinosulfone has the formula —NRC(═NR)NRSO2—Rb;
thioaryl having the formula “—S-alkyl”, wherein alkyl is R101;
substituted thioalkyl has the formula “—S-substituted alkyl”, wherein substituted alkyl is R102;
thiocycloalkyl has the formula “—S-cycloalkyl”, wherein cycloalkyl is R103;
substituted thiocycloalkyl has the formula “—S-substituted cycloalkyl”, wherein substituted cycloalkyl is R104;
thioaryl has the formula “—S-aryl”, wherein aryl is R107;
substituted thioaryl has the formula “—S-substituted aryl”, wherein substituted aryl is R108;
thioheteroaryl has the formula “—S-heteroaryl”, wherein heteroaryl is R109;
substituted thioheteroaryl has the formula “—S-substituted heteroaryl”, wherein substituted heteroaryl is R110;
thioheterocyclic has the formula “—S-heterocyclic”, wherein heterocyclic is R105;
and
substituted thioheterocyclic has the formula “—S-substituted heterocyclic”, wherein substituted heterocyclic is R106;
wherein
each R is independently hydrogen or R101;
each Rb is a member independently selected from R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111, R112, R113 and R114;
each Rc is a member independently selected from H, R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111, R112, R113 and R114;
and
each Rf is independently hydrogen, R101 or a blocking group selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl.

369 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/582,293Filed 16 Oct 2006 · continuation
Priority: 22 Jan 1999
Published: US 2007/0099921 A13 May 2007
Granted: 22 Jun 2010
Term ends: Not estimatedThe source records don’t support an estimate.

Classification75 codes

A61K 31/425
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: thiazoles
A61K 31/41
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having five-membered rings with two or more ring hetero atoms, at least…
A61K 31/427
Thiazoles: not condensed and containing further heterocyclic rings
A61K 31/433
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: thidiazoles

Family

Application60/116,923Us provisional application · filed 22 Jan 1999
Application60/160,999Us provisional application · filed 21 Oct 1999
Application09/489,377Parent of this division · filed 21 Jan 2000
Application10/218,366Parent of this division · filed 15 Aug 2002
Application11/033,079Parent of this continuation · filed 10 Jan 2005
US 2007/0099921 A1Pre-grant publication · published 3 May 2007
US 7,378,529 B2Parent of this continuation
US 6,911,439 B2Parent of this division
Application11/033,079Parent of this division
US 6,492,372 B1Parent of this division
US 2003/0125324 A1Published application
US 2005/0203093 A1Published application
US 7,741,328 B2This patent

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

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Abstract

A compound of formula IIa:

or a pharmaceutically acceptable salt thereof,
wherein
ring A forms a pyrimidine ring, optionally substituted with 1 or 2 substituents selected from the group consisting of R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, alkoxy, substituted alkoxy, amino, substituted amino and halogen,
R3 is —(CH2)x—Ar—R9, wherein
Ar is R107 or R109;
x is an integer from 0 to 4;
and
R9 is selected from the group consisting of acyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, oxycarbonylamino, thioamidino, thiocarbonylamino, aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylamino and oxysulfonyl;
R3′ is hydrogen;
Q is —NR4—, wherein R4 is hydrogen or R101;
R5 is selected from the group consisting of R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111, R112, R115 and R116;
R6 is selected from the group consisting of hydrogen, R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R115 and R116;
and
X is selected from the group consisting of hydroxyl, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, cycloalkoxy, substituted cycloalkoxy, cycloalkenoxy, substituted cycloalkenoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy and —NR″R″, wherein each R″ is independently selected from the group consisting of hydrogen, R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111 and R112,
wherein
R101 is alkyl of from 1 to 10 carbon atoms;
R102 is substituted alkyl of from 1 to 10 carbon atoms, having from 1 to 5 substituents selected from the group consisting of
(1) R200;
(2) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(3) amino groups blocked by blocking groups selected from the group consisting of tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(4) R300;
R103 is cycloalkyl of from 3 to 8 carbon atoms;
R104 is substituted cycloalkyl of from 3 to 8 carbon atoms, having from 1 to 5 substituents selected from the group consisting of
(1) R200;
(2) oxo (═O);
(3) thioxo (═S);
(4) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(5) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(6) R300;
R105 is heterocyclic referring to a saturated or unsaturated group having from 1 to 10 carbon atoms and from 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen, and having a single ring or multiple fused rings, wherein in fused ring systems one or more of the rings can be aryl (R107) or heteroaryl (R109);
R106 is substituted heterocyclic of from 1 to 10 carbon atoms and from 1 to 4 heteroatoms, substituted with from 1 to 3 substituents selected from the group consisting of
(1) R200;
(2) oxo (═O);
(3) thioxo (═S);
(4) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(5) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(6) R300;
R107 is aryl, wherein aryl is an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring or multiple condensed rings, wherein the condensed rings may or may not be aromatic;
R108 is substituted aryl, wherein substituted aryl is aryl substituted with from 1 to 3 substituents selected from the group consisting of
(1) R201;
(2) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R105, R106, R107, R108, R109 and R110;
(3) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(4) —SO2NRR;
R109 is heteroaryl of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring or oxides thereof, having a single ring or multiple condensed rings;
R110 is substituted heteroaryl of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, substituted with from 1 to 3 substituents selected from the group consisting of
(1) R201;
(2) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(3) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(4) —SO2NRR;
R111 is alkenyl of from 2 to 10 carbon atoms and from 1 to 2 sites of alkenyl unsaturation;
R112 is substituted alkenyl, wherein substituted alkenyl is alkenyl substituted with from 1 to 5 substituents selected from the group consisting of
(1) R200;
(2) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(3) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(4) R300;
R113 is alkynyl of from 2 to 10 carbon atoms and from 1 to 2 sites of alkynyl unsaturation;
R114 is substituted alkynyl, wherein substituted alkynyl is alkynyl substituted with from 1 to 5 substituents selected from the group consisting of
(1) R200;
(2) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(3) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(4) R300;
R115 is cycloalkenyl, wherein cycloalkenyl is a cyclic alkenyl group of from 3 to 8 carbon atoms having single or multiple unsaturation, and which is not aromatic;
R116 is substituted cycloalkenyl of from 3 to 8 carbon atoms, having from 1 to 5 substituents selected from the group consisting of
(1) R200;
(2) oxo (═O);
(3) thioxo (═S);
and
(4) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(5) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(6) R300;
wherein
R200 is a member selected from
(1) alkoxy;
(2) substituted alkoxy;
(3) acyl;
(4) acylamino;
(5) thiocarbonylamino;
(6) acyloxy;
(7) amino;
(8) amidino;
(9) alkylamidino wherein alkyl is R101;
(10) thioamidino;
(11) aminoacyl;
(12) aminocarbonylamino;
(13) aminothiocarbonylamino;
(14) aminocarbonyloxy;
(15) R107;
(16) R108;
(17) aryloxy;
(18) substituted aryloxy;
(19) aryloxyaryl;
(20) substituted aryloxyaryl;
(21) halogen;
(22) hydroxyl;
(23) cyano;
(24) nitro;
(25) carboxyl;
(26) carboxylalkyl wherein alkyl is R101;
(27) carboxyl-substituted alkyl wherein substituted alkyl is R102;
(28) carboxyl-cycloalkyl wherein cycloalkyl is R103;
(29) carboxyl-substituted cycloalkyl wherein substituted cycloalkyl is R104;
(30) carboxylaryl wherein aryl is R107;
(31) carboxyl-substituted aryl wherein substituted aryl is R108;
(32) carboxylheteroaryl wherein heteroaryl is R109;
(33) carboxyl-substituted heteroaryl wherein substituted heteroaryl is R110;
(34) carboxylheterocyclic wherein heterocyclic is R105;
(35) carboxyl-substituted heterocyclic wherein substituted heterocyclic is R106;
(36) R103;
(36) R104;
(38) guanidino;
(39) guanidinosulfone;
(40) thiol having the formula —SH;
(41) thioaryl;
(42) substituted thioalkyl;
(43) thioaryl;
(44) substituted thioaryl;
(45) thiocycloalkyl;
(46) substituted thiocycloalkyl;
(47) thioheteroaryl;
(48) substituted thioheteroaryl;
(49) thioheterocyclic;
(50) substituted thioheterocyclic;
(51) R109;
(52) R110;
(53) R105;
(54) R106;
(55) cycloalkoxy;
(56) substituted cycloalkoxy;
(57) heteroaryloxy;
(58) substituted heteroaryloxy;
(59) heterocyclyloxy;
(60) substituted heterocyclyloxy;
(61) oxycarbonylamino;
(62) oxythiocarbonylamino;
(63) —OS(O)2-alkyl, wherein alkyl is R101;
(64) —OS(O)2-substituted alkyl wherein substituted alkyl is R102;
(65) —OS(O)2-aryl, wherein aryl is R107;
(66) —OS(O)2-substituted aryl wherein substituted aryl is R108;
(67) —OS(O)2-heteroaryl wherein heteroaryl is R109;
(68) —OS(O)2-substituted heteroaryl wherein substituted heteroaryl is R110;
(69) —OS(O)2-heterocyclic wherein heterocyclic is R105;
(70) —OS(O)2-substituted heterocyclic wherein substituted heterocyclic is R106;
(71) —NRR where R is hydrogen or R101;
(72) —NRS(O)2-alkyl, wherein alkyl is R101;
(73) —NRS(O)2-substituted alkyl wherein substituted alkyl is R102;
(74) —NRS(O)2-aryl, wherein aryl is R107;
(75) —NRS(O)2-substituted aryl wherein substituted aryl is R108;
(76) —NRS(O)2-heteroaryl wherein heteroaryl is R109;
(77) —NRS(O)2-substituted heteroaryl wherein substituted heteroaryl is R110;
(78) —NRS(O)2-heterocyclic wherein heterocyclic is R105;
(79) —NRS(O)2-substituted heterocyclic wherein substituted heterocyclic is R106;
(80) —NRS(O)2—NR-alkyl, wherein alkyl is R101;
(81) —NRS(O)2—NR-substituted alkyl wherein substituted alkyl is R102;
(82) —NRS(O)2—NR-aryl, wherein aryl is R107;
(83) —NRS(O)2—NR-substituted aryl wherein substituted aryl is R108;
(84) —NRS(O)2—NR-heteroaryl wherein heteroaryl is R109;
(85) —NRS(O)2—NR-substituted heteroaryl wherein substituted heteroaryl is R110;
(86) —NRS(O)2—NR-heterocyclic wherein heterocyclic is R105;
(87) —NRS(O)2—NR-substituted heterocyclic wherein substituted heterocyclic is R106,
(88) mono- and di-alkylamino, wherein alkyl is R101;
(89) mono- and di-(substituted alkyl)amino, wherein substituted alkyl is R102;
(90) mono- and di-arylamino wherein aryl is R107;
(91) mono- and di-substituted arylamino wherein substituted aryl is R108;
(92) mono- and di-heteroarylamino wherein heteroaryl is R109;
(93) mono- and di-substituted heteroarylamino wherein substituted heteroaryl is R110;
(94) mono- and di-heterocyclic amino wherein heterocyclic is R105;
and
(95) mono- and di-substituted heterocyclic amino wherein substituted heterocyclic is R106;
R201 is a member selected from
(1) hydroxyl;
(2) acyl;
(3) acylamino;
(4) thiocarbonylamino;
(5) acyloxy;
(6) R101;
(7) R102;
(8) alkoxy;
(9) substituted alkoxy;
(10) R111;
(11) R112;
(12) R113;
(13) R114;
(14) amidino;
(15) alkylamidino, wherein alkyl is R101;
(16) thioamidino;
(17) amino;
(18) aminoacyl;
(19) aminocarbonyloxy;
(20) aminocarbonylamino;
(21) aminothiocarbonylamino;
(22) R107;
(23) R108;
(24) aryloxy;
(25) substituted aryloxy;
(26) cycloalkoxy;
(27) substituted cycloalkoxy;
(28) heteroaryloxy;
(29) substituted heteroaryloxy;
(30) heterocyclyloxy;
(31) substituted heterocyclyloxy;
(32) carboxyl;
(33) carboxylalkyl wherein alkyl is R101;
(34) carboxyl-substituted alkyl wherein substituted alkyl is R102;
(35) carboxyl-cycloalkyl wherein cycloalkyl is R103;
(36) carboxyl-substituted cycloalkyl wherein substituted cycloalkyl is R104;
(37) carboxylaryl wherein aryl is R107;
(38) carboxyl-substituted aryl wherein substituted aryl is R108;
(39) carboxylheteroaryl wherein heteroaryl is R109;
(40) carboxyl-substituted heteroaryl wherein substituted heteroaryl is R110;
(41) carboxylheterocyclic wherein heterocyclic is R105;
(42) carboxyl-substituted heterocyclic wherein substituted heterocyclic is R106;
(43) carboxylamido;
(44) cyano;
(45) thiol having the formula —SH;
(46) thioalkyl;
(47) substituted thioalkyl;
(48) thioaryl;
(49) substituted thioaryl
(50) thioheteroaryl;
(51) substituted thioheteroaryl;
(52) thiocycloalkyl;
(53) substituted thiocycloalkyl;
(54) thioheterocyclic;
(55) substituted thioheterocyclic;
(56) R103;
(57) R104;
(58) guanidino;
(59) guanidinosulfone;
(60) halogen;
(61) nitro;
(62) R109;
(63) R110;
(64) R105;
(65) R106;
(66) cycloalkoxy;
(67) substituted cycloalkoxy;
(68) heteroaryloxy;
(69) substituted heteroaryloxy;
(70) heterocyclyloxy;
(71) substituted heterocyclyloxy;
(72) oxycarbonylamino;
(73) oxythiocarbonylamino;
(74) —S(O)2-alkyl wherein alkyl is R101;
(75) —S(O)2-substituted alkyl wherein substituted alkyl is R102;
(76) —S(O)2-cycloalkyl wherein cycloalkyl is R103;
(77) —S(O)2-substituted cycloalkyl wherein substituted cycloalkyl is R104;
(78) —S(O)2-alkenyl wherein alkenyl is R111;
(79) —S(O)2-substituted alkenyl wherein substituted alkenyl is R112;
(80) —S(O)2-aryl wherein aryl is R107;
(81) —S(O)2-substituted aryl wherein substituted aryl is R108;
(82) —S(O)2-heteroaryl wherein heteroaryl is R109;
(83) —S(O)2-substituted heteroaryl wherein substituted heteroaryl is R110;
(84) —S(O)2-heterocyclic wherein heterocyclic is R105;
(85) —S(O)2-substituted heterocyclic wherein substituted heterocyclic is R106;
(86) —OS(O)2-alkyl wherein alkyl is R101;
(87) —OS(O)2-substituted alkyl wherein substituted alkyl is R102;
(88) —OS(O)2-aryl wherein aryl is R107;
(89) —OS(O)2-substituted aryl wherein substituted aryl is R108;
(90) —OS(O)2-heteroaryl wherein heteroaryl is R109;
(91) —OS(O)2-substituted heteroaryl wherein substituted heteroaryl is R110;
(92) —OS(O)2-heterocyclic wherein heterocyclic is R105;
(93) —OS(O)2-substituted heterocyclic wherein substituted heterocyclic is R106;
(94) —OS(O)2—NRR where R is hydrogen or R101;
(95) —NRS(O)2-alkyl wherein alkyl is R101;
(96) —NRS(O)2-substituted alkyl wherein substituted alkyl is R102;
(97) —NRS(O)2-aryl wherein aryl is R107;
(98) —NRS(O)2-substituted aryl wherein substituted aryl is R108;
(99) —NRS(O)2-heteroaryl wherein heteroaryl is R109;
(100) —NRS(O)2-substituted heteroaryl wherein substituted heteroaryl is R110;
(101) —NRS(O)2-heterocyclic wherein heterocyclic is R105;
(102) —NRS(O)2-substituted heterocyclic wherein substituted heterocyclic is R106;
(103) —NRS(O)2—NR-alkyl wherein alkyl is R101;
(104) —NRS(O)2—NR-substituted alkyl wherein substituted alkyl is R102;
(105) —NRS(O)2—NR-aryl wherein aryl is R107;
(106) —NRS(O)2—NR-substituted aryl wherein substituted aryl is R108;
(107) —NRS(O)2—NR-heteroaryl wherein heteroaryl is R109;
(108) —NRS(O)2—NR-substituted heteroaryl wherein substituted heteroaryl is R110;
(109) —NRS(O)2—NR-heterocyclic wherein heterocyclic is R105;
(110) —NRS(O)2—NR-substituted heterocyclic wherein substituted heterocyclic is R106,
(111) mono- and di-alkylamino, wherein alkyl is R101;
(112) mono- and di-
(substituted alkyl)amino, wherein substituted alkyl is R102;
(113) mono- and di-arylamino wherein aryl is R107;
(114) mono- and di-substituted arylamino wherein substituted aryl is R108;
(115) mono- and di-heteroarylamino wherein heteroaryl is R109;
(116) mono- and di-substituted heteroarylamino wherein substituted heteroaryl is R110;
(117) mono- and di-heterocyclic amino wherein heterocyclic is R105;
(118) mono- and di-substituted heterocyclic amino wherein substituted heterocyclic is R106;
R300 is a member selected from
(i) —SO2-alkyl wherein alkyl is R101;
(ii) —SO2-substituted alkyl wherein substituted alkyl is R102;
(iii) —SO2-alkenyl wherein alkenyl is R111;
(iv) —SO2-substituted alkenyl wherein substituted alkenyl is R112;
(v) —SO2-cycloalkyl wherein cycloalkyl is R103;
(vi) —SO2-substituted cycloalkyl wherein substituted cycloalkyl is R104;
(vii) —SO2-aryl wherein aryl is R107;
(viii) —SO2-substituted aryl wherein substituted aryl is R108;
(ix) —SO2-heteroaryl wherein heteroaryl is R109;
(x) —SO2-substituted heteroaryl wherein substituted heteroaryl is R110;
(xi) —SO2-heterocyclic wherein heterocyclic is R105;
(xii) —SO2-substituted heterocyclic wherein substituted heterocyclic is R106;
and
(xiii) —SO2NRR;
alkoxy has the formula “alkyl-O—”, wherein alkyl is R101;
substituted alkoxy has the formula “substituted alkyl-O—”, wherein substituted alkyl is R102;
cycloalkoxy has the formula “—O-cycloalkyl”, wherein cycloalkyl is R103;
substituted cycloalkoxy has the formula “—O-substituted cycloalkyl”, wherein substituted cycloalkyl is R104;
alkenoxy has the formula “alkenyl-O—”, wherein alkenyl is R111;
substituted alkenoxy has the formula “substituted alkenyl-O—”, wherein substituted alkenyl is R112;
cycloalkenoxy has the formula “cycloalkenyl-O—”, wherein cycloalkenyl is R115;
substituted cycloalkenoxy has the formula “substituted cycloalkenyl-O—”, wherein substituted cycloalkenyl is R116;
aryloxy has the formula “aryl-O—”, wherein aryl is R107;
substituted aryloxy has the formula “substituted aryl-O—”, wherein substituted aryl is R108;
heteroaryloxy has the formula “—O-heteroary”, wherein heteroaryl is R109;
substituted heteroaryloxy has the formula “—O-substituted heteroaryl”, wherein substituted heteroaryl is R110;
heterocyclyloxy has the formula “—O-heterocyclic”, wherein heterocyclic is R105;
substituted heterocyclyloxy has the formula “—O-substituted heterocyclic”, wherein substituted heterocyclic is R106;
aryloxyaryl has the formula “aryl-O-aryl”, wherein each aryl is R107;
substituted aryloxyaryl has the formula “aryl-O-aryl”, wherein each aryl is R107, substituted on one or both aryl rings with from 1 to 3 substituents selected from the group consisting of
(1) R201;
(2) unsymmetric di-substituted amines having different substituents selected from the group consisting of R101, R102, R107, R108, R109, R110, R105 and R106;
(3) amino groups blocked by blocking groups selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl;
and
(4) —SO2NRR;
acyl is Rc—C(O)—;
acylamino is selected from the group —C(O)NRcRc, wherein each Rc is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
thiocarbonylamino is selected from the group —C(S)NRcRc, wherein each Rc is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic R106;
acyloxy is selected from Rb—C(O)O—;
oxysulfonyl has the formula Rb—SO2O—;
amino has the formula —NH2;
substituted amino has the formula —NRdRd, where each Rd is independently selected from the group consisting of hydrogen, R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111, R112, R113, R114 and —SO2—Re, wherein Re is a member selected from R101, R102, R103, R104, R105, R106, R107, R109, R110, R111 and R112;
or the Rd groups can be joined together with the nitrogen atom to form a heterocyclic or a substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106,
provided that both Rd groups are not hydrogen;
amidino has the formula H2NC(═NH)—;
alkyl amidino is “alkylHNC(═NH)—”, wherein alkyl is R101;
thioamidino has the formula RSC(═NH)—;
aminoacyl has the formula —NRC(O)Rb;
aminosulfonyl having the formula —NRSO2Rb;
aminocarbonyloxy having the formula —NRC(O)O2Rb;
aminosulfonyloxy has the formula —NRSO2O2Rb;
oxycarbonylamino has the formula —OC(O)NH2, —OC(O)NRR or —OC(O)NRRb, wherein each R is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
oxythiocarbonylamino has the formula —OC(S)NH2, —OC(S)NRR or —OC(S)NRRb, wherein each R is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
aminocarbonylamino has the formula —NRfC(O)NRfRf or —NRfC(O)NRfRb, wherein each Rf is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
aminothiocarbonylamino has the formula —NRfC(S)NRfRf or —NRfSO2NRfRb, wherein each Rf is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
aminosulfonylamino has the formula —NRfSO2NRfRf or —NRfSO2NRfRb, wherein each Rf is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
oxysulfonylamino has the formula —OSO2NH2, —OSO2NRR or —OSO2NRRb, wherein each R is optionally joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring, wherein heterocyclic is R105 and substituted heterocyclic is R106;
halogen is fluoro, chloro, bromo or iodo;
guanidino has the formula —NRfC(═NRf)NRfRf or —NRfC(═NRf)NRfRb;
guanidinosulfone has the formula —NRC(═NR)NRSO2—Rb;
thioaryl having the formula “—S-alky”, wherein alkyl is R101;
substituted thioalkyl has the formula “—S-substituted alkyl”, wherein substituted alkyl is R102;
thiocycloalkyl has the formula “—S-cycloalkyl”, wherein cycloalkyl is R103;
substituted thiocycloalkyl has the formula “—S-substituted cycloalkyl”, wherein substituted cycloalkyl is R104;
thioaryl has the formula “—S-aryl”, wherein aryl is R107;
substituted thioaryl has the formula “—S-substituted aryl”, wherein substituted aryl is R108;
thioheteroaryl has the formula “—S-heteroaryl”, wherein heteroaryl is R109;
substituted thioheteroaryl has the formula “—S-substituted heteroaryl”, wherein substituted heteroaryl is R110;
thioheterocyclic has the formula “—S-heterocyclic”, wherein heterocyclic is R105;
and
substituted thioheterocyclic has the formula “—S-substituted heterocyclic”, wherein substituted heterocyclic is R106;
wherein
each R is independently hydrogen or R101;
each Rb is a member independently selected from R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111, R112, R113 and R114;
each Rc is a member independently selected from H, R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111, R112, R113 and R114;
and
each Rf is independently hydrogen, R101 or a blocking group selected from tert butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl.

371 more elements

Facts

Application

11/582,293Filed 16 Oct 2006 · continuation

Priority

22 Jan 1999

Published

US 2007/0099921 A13 May 2007

Granted

22 Jun 2010

Term ends

Not estimatedThe source records don’t support an estimate.

Classification75 codes

A61K 31/425
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: thiazoles
A61K 31/41
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having five-membered rings with two or more ring hetero atoms, at least…
A61K 31/427
Thiazoles: not condensed and containing further heterocyclic rings
A61K 31/433
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: thidiazoles

Family

Application60/116,923Us provisional application · filed 22 Jan 1999

Application60/160,999Us provisional application · filed 21 Oct 1999

Application09/489,377Parent of this division · filed 21 Jan 2000

Application10/218,366Parent of this division · filed 15 Aug 2002

Application11/033,079Parent of this continuation · filed 10 Jan 2005

US 2007/0099921 A1Pre-grant publication · published 3 May 2007

US 7,378,529 B2Parent of this continuation

US 6,911,439 B2Parent of this division

Application11/033,079Parent of this division

US 6,492,372 B1Parent of this division

US 2003/0125324 A1Published application

US 2005/0203093 A1Published application

US 7,741,328 B2This patent

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