Acetyl 2-hydroxy-1,3-diaminoalkanes

A compound of the formula I:

• or pharmaceutically acceptable salts thereof, wherein
• Z is hydrogen, or
• Z is (C3-C7 cycloalkyl)0-1(C1-C6 alkyl)-, (C3-C7 cycloalkyl)0-1(C2-C6 alkenyl)-, (C3-C7 cycloalkyl)0-1(C2-C6 alkynyl)- or (C3-C7 cycloalkyl)-, wherein each of said groups is optionally substituted with 1, 2, or 3 Rz groups, wherein 1 or 2 methylene groups within said (C3-C7 cycloalkyl)0-1(C1-C6 alkyl)-, (C3-C7 cycloalkyl)0-1(C2-C6 alkenyl)-, (C3-C7 cycloalkyl)0-1(C2-C6 alkynyl)- or (C3-C7 cycloalkyl)- groups are optionally replaced with —(C═O)—;
• Rz at each occurrence is independently halogen (in one aspect, F or Cl), —OH, —SH, —CN, —CF3, —OCF3, C1-C6 alkoxy, C3-C7 cycloalkyl, C3-C7 cycloalkoxy or —NR100R101;
• R100 and R101 at each occurrence are independently H, C1-C6 alkyl, phenyl, CO(C1-C6alkyl) or SO2C1-C6 alkyl;
• X is —(C═O)— or —(SO2)—;
• R1 is C1-C10 alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, ═O, —SH, —CN, —CF3, —C3-7 cycloalkyl, —C1-C4 alkoxy, amino, mono- or dialkylamino, aryl, heteroaryl, and heterocycloalkyl,
• wherein each aryl group is optionally substituted with 1, 2 or 3 R50 groups;
• each heteroaryl is optionally substituted with 1 or 2 R50 groups;
• and each heterocycloalkyl group is optionally substituted with 1 or 2 groups that are independently R50 or ═O;
• R50 is selected from halogen, OH, SH, CN, —CO—(C1-C4 alkyl), —NR7R8, —S(O)0-2—(C1-C4 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and C3-C8 cycloalkyl;
• wherein
• the alkyl, alkenyl, alkynyl, alkoxy and cycloalkyl groups are optionally substituted with 1 or 2 substituents independently selected from C1-C4 alkyl, halogen, OH, —NR5R6, CN, C1-C4 haloalkoxy, NR7R8, and C1-C4 alkoxy;
• wherein
• R5 and R6 are independently H or C1-C6 alkyl;
• or
• R5 and R6 and the nitrogen to which they are attached form a 5 or 6 membered heterocycloalkyl ring;
• R7 and R8 are independently selected from H;
• —C1-C4 alkyl optionally substituted with 1, 2, or 3 groups independently selected from —OH, —NH2, and halogen;
• —C3-C6 cycloalkyl;
• —(C1-C4 alkyl)-β—(C1-C4 alkyl);
• —C2-C4 alkenyl;
• and —C2-C4 alkynyl;
• R2 and R3 are independently selected from H;
• F;
• —C1-C6 alkyl optionally substituted with —F, —OH, —C≡N, —CF3, C1-C3 alkoxy, or —NR5R6;
• —(CH2)0-2—R17;
• —(CH2)0-2—R18;
• —C2-C6 alkenyl or C2-C6 alkynyl, wherein the alkenyl and alkynyl groups are optionally substituted with 1 or 2 groups that are independently —F, —OH, —C≡N, —CF3 or C1-C3 alkoxy;
• —(CH2)0-2—C3-C7 cycloalkyl, which is optionally substituted with 1 or 2 groups that are independently —F, —OH, —C≡N, —CF3, C1-C3 alkoxy and —NR5R6;
• R17 at each occurrence is an aryl group (preferably selected from phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl and tetralinyl) wherein said aryl group is optionally substituted with one or two groups that are independently —C1-C3 alkyl;
• —C1-C4 alkoxy;
• CF3;
• —C2-C6 alkenyl or —C2-C6 alkynyl each of which is optionally substituted with one substituent selected from F, OH, C1-C3 alkoxy;
• halogen;
• OH;
• —C≡N;
• —C3-C7 cycloalkyl;
• —CO—(C1-C4 alkyl);
• or —SO2—(C1-C4 alkyl);
• R18 is a heteroaryl group (preferably selected from pyridinyl, pyrimidinyl, quinolinyl, indolyl, pyridazinyl, pyrazinyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, furanyl, thienyl, pyrrolyl, oxadiazolyl or thiadiazolyl) wherein said heteroaryl groups are optionally substituted with one or two groups that are independently —C1-C6 alkyl optionally substituted with one substituent selected from OH, CF3, C1-C3 alkoxy, and —NR5R6;
• R15 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkyl, hydroxy C1-C6 alkyl, halo C1-C6 alkyl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from halogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, and NH2, and —R26-R27;
• wherein
• R26 is selected from a bond, —C(O)—, —SO2—, —CO2—, —C(O)NR5—, and —NR5C(O)—,
• R27 is selected from C1-C6 alkyl, C1-C6 alkoxy, aryl C1-C6 alkyl, heterocycloalkyl, and heteroaryl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently C1-C4 alkyl, C1-C4 alkoxy, halogen, haloalkyl, hydroxyalkyl, —NR5R6, or —C(O)NR5R6;
• or
• R2, R3 and the carbon to which they are attached form a C3-C7 carbocycle, wherein 1, 2, or 3 carbon atoms are optionally replaced by groups that are independently selected from —O—, —S—, —SO2—, —C(O)—, or —NR7—;
• Rc is selected from —(CH2)0-3—(C3-C6) cycloalkyl wherein the cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from —R205;
• and —CO2—(C1-C4 alkyl);
• —(CR245R250)0-4-aryl;
• —(CR245R250)0-4-heteroaryl;
• —(CR245R250)0-4-heterocycloalkyl;
• —(CR245R250)0-4-aryl-heteroaryl;
• —(CR245R250)0-4-aryl-heterocycloalkyl;
• —(CR245R250)0-4-aryl-aryl;
• —(CR245R250)0-4-heteroaryl-aryl;
• —(CR245R250)0-4-heteroaryl-heterocycloalkyl;
• —(CR245R250)0-4-heteroaryl-heteroaryl;
• —CHR245—CHR250-aryl;
• —(CR245R250)0-4—(CR245R250)0-4-heterocycloalkyl-heterocycloalkyl;
• —(CR245R250)0-4-heterocycloalkyl-aryl;
• a monocyclic or bicyclic ring of 5, 6, 7 8, 9, or 10 carbons fused to 1 or 2 aryl (preferably phenyl), heteroaryl (preferably pyridyl, imidazolyl, thienyl, thiazolyl, or pyrimidyl), or heterocycloalkyl (preferably piperidinyl or piperazinyl) groups;
• wherein 1, 2 or 3 carbons of the monocyclic or bicyclic ring are optionally replaced with —NH—, —N(CO)0-1R215—N(CO)0-1R220—, —O—, or —S(═O)0-2—, and wherein the monocyclic or bicyclic ring is optionally substituted with 1, 2 or 3 groups that are independently —R205, —R245, —R250 or ═O;
• and —C2-C6 alkenyl optionally substituted with 1, 2, or 3 R205 groups;
• wherein each aryl or heteroaryl group attached directly or indirectly to the —(CR245R250)0-4 group is optionally substituted with 1, 2, 3 or 4 R200 groups;
• wherein each heterocycloalkyl attached directly or indirectly to the —(CR245R250)0-4 group is optionally substituted with 1, 2, 3, or 4 R210;
• R200 at each occurrence is independently selected from —C1-C6 alkyl optionally substituted with 1, 2, or 3 R205 groups;
• —OH;
• —NO2;
• -halogen;
• —C≡N;
• —(CH2)0-4—CO—NR220R225;
• —(CH2)0-4—CO—(C1-C8 alkyl);
• —(CH2)0-4—CO—(C2-C8 alkenyl);
• —(CH2)0-4—CO—(C2-C8 alkynyl);
• —(CH2)0-4—CO—(C3-C7 cycloalkyl);
• —(CH2)0-4—(CO)0-1-aryl (preferably phenyl);
• —(CH2)0-4—(CO)0-1-heteroaryl (preferably pyridyl, pyrimidyl, furanyl, imidazolyl, thienyl, oxazolyl, thiazolyl, or pyrazinyl);
• —(CH2)0-4—(CO)0-1-heterocycloalkyl (preferably imidazolidinyl, piperazinyl, pyrrolidinyl, piperidinyl, or tetrahydropyranyl);
• —(CH2)0-4—CO2R215;
• —(CH2)0-4—SO2—NR220R225;
• —(CH2)0-4—S(O)0-2—(C1-C8 alkyl);
• —(CH2)0-4—S(O)0-2—(C3-C7 cycloalkyl);
• —(CH2)0-4—N(H or R215)—CO2R215;
• —(CH2)0-4—N(H or R215) —SO2—R220;
• —(CH2)0-4—N(H or R215)—CO—N(R215)2;
• —(CH2)0-4—N(—H or R215)—CO—R220;
• —(CH2)0-4—NR220R225;
• —(CH2)0-4—O—CO—(C1-C6 alkyl);
• —(CH2)0-4—O—(R215);
• —(CH2)0-4—S—(R215);
• —(CH2)0-4—O—(C1-C6 alkyl optionally substituted with 1, 2, 3, or 5 —F);
• —C2-C6 alkenyl optionally substituted with 1 or 2 R205 groups;
• —C2-C6 alkynyl optionally substituted with 1 or 2 R205 groups;
• adamantly, and —(CH2)0-4—C3-C7 cycloalkyl;
• each aryl and heteroaryl group included within R200 is optionally substituted with 1, 2, or 3 groups that are independently —R205, —R210 or —C1-C6 alkyl substituted with 1, 2, or 3 groups that are independently R205 or R210;
• each heterocycloalkyl group included within R200 is optionally substituted with 1, 2, or 3 groups that are independently R210;
• R205 at each occurrence is independently selected from —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —C1-C6 haloalkoxy, —(CH2)0-3(C3-C7 cycloalkyl), -halogen, —(CH2)0-6—OH, —O-phenyl, OH, SH, —(CH2)0-6—C≡N, —(CH2)0-6—C(═O)NR235R240, —CF3, —C1-C6 alkoxy, C1-C6 alkoxycarbonyl, and —NR235R240;
• R210 at each occurrence is independently selected from —C1-C6 alkyl optionally substituted with 1, 2, or 3 R205 groups;
• —C2-C6 alkenyl optionally substituted with 1, 2, or 3 R205 groups;
• C1-C6 alkanoyl;
• —SO2—(C1-C6 alkyl);
• —C2-C6 alkynyl optionally substituted with 1, 2, or 3 R205 groups;
• -halogen;
• —C1-C6 alkoxy;
• —C1-C6 haloalkoxy;
• —NR220R225;
• —OH;
• —C≡N;
• —C3-C7 cycloalkyl optionally substituted with 1, 2, or 3 R205 groups;
• —CO—(C1-C4 alkyl);
• —SO2—NR235R240;
• —CO—NR235R240;
• —SO2—(C1-C4 alkyl);
• and ═O;
• R215 at each occurrence is independently selected from —C1-C6 alkyl, —(CH2)0-2— (aryl), —C2-C6 alkenyl, —C2-C6 alkynyl, —C3-C7 cycloalkyl, —(CH2)0-2-(heteroaryl) and —(CH2)0-2—(heterocycloalkyl);
• wherein the aryl group included within R215 is optionally substituted with 1, 2, or 3 groups that are independently —R205 or —R210;
• wherein the heterocycloalkyl and heteroaryl groups included within R215 are optionally substituted with 1, 2, or 3 R210;
• R220 and R225 at each occurrence are independently H, —C1-C6 alkyl, —CHO, hydroxy C1-C6 alkyl, C1-C6 alkoxycarbonyl, -amino C1-C6 alkyl, —SO2—C1-C6 alkyl, C1-C6 alkanoyl optionally substituted with up to three halogens, —C(O)NH2, —C(O)NH(C1-C6 alkyl), —C(O)N(C1-C6 alkyl)(C1-C6 alkyl), -halo C1-C6 alkyl, —(CH2)0-2—(C3-C7 cycloalkyl), —(C1-C6 alkyl)-O—(C1-C6 alkyl), —C2-C6 alkenyl, —C2-C6 alkynyl, -aryl (preferably phenyl), -heteroaryl, or -heterocycloalkyl;
• wherein the aryl, heteroaryl and heterocycloalkyl groups included within R220 and R225 is optionally substituted with 1, 2, or 3 R270 groups,
• R270 at each occurrence is independently —R205, —C1-C6 alkyl optionally substituted with 1, 2, or 3 R205 groups;
• —C2-C6 alkenyl optionally substituted with 1, 2, or 3 R205 groups;
• —C2-C6 alkynyl optionally substituted with 1, 2, or 3 R205 groups;
• —phenyl;
• -halogen;
• —C1-C6 alkoxy;
• —C1-C6 haloalkoxy;
• —NR235R240;
• —OH;
• —C≡N;
• —C3-C7 cycloalkyl optionally substituted with 1, 2, or 3 R205 groups;
• —CO—(C1-C4 alkyl);
• —SO2—NR235R240;
• —CO—NR235R240;
• —SO2—(C1-C4 alkyl);
• and ═O;
• R235 and R240 at each occurrence are independently —H, —C1-C6 alkyl, C2-C6 alkanoyl, —SO2—(C1-C5 alkyl), or -phenyl;
• R245 and R250 at each occurrence are independently selected from H, —(CH2)0-4CO2C1-C4 alkyl, —(CH2)0-4C(═O)C1-C4 alkyl, —C1-C4 alkyl, —C1-C4 hydroxyalkyl, —C1-C4 alkoxy, —C1-C4 haloalkoxy, —(CH2)0-4—C2-C7 cycloalkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —(CH2)0-4 aryl, —(CH2)0-4 heteroaryl, and —(CH2)0-4 heterocycloalkyl, or
• R245 and R250 are taken together with the carbon to which they are attached to form a monocycle or bicycle of 3, 4, 5, 6, 7 or 8 carbon atoms, where 1, 2, or 3 carbon atoms are optionally replaced by 1, 2, or 3 groups that are independently —O—, —S—, —SO2—, —C(O)—, —NR220—, or —NR220R220— wherein both R220 groups are alkyl;
• and wherein the ring is optionally substituted with 1, 2, 3, 4, 5, or 6 groups that are independently C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), —NH—C(O)C1-C6 alkyl, —NH—SO2—(C1-C6 alkyl), or halogen;
• wherein the aryl, heteroaryl or heterocycloalkyl groups included within R245 and R250 are optionally substituted with 1, 2, or 3 groups that are independently halogen, C1-6 alkyl, CN or OH.