Protected monomers

1 . A protected monomer having a formula (I)

wherein,

B is selected from the consisting of:

X 2 is an ortho ester protecting group, hydrogen, ethers, alkyl ethers, esters, halogens, protected amines, or protected hydroxyl moieties;

X 3 is —O—P(OR 27 )N(R 28 ) 2 or —O-L-R 29 ;

X 5′ , X 5″ , X 5′″ include at least one alkoxy or siloxy substituent;

R 1 is hydrogen or C 1 -C 4 alkyl;

R 2 is hydrogen, C 1 -C 4 alkyl, or C 2 -C 6 alkenyl optionally substituted with hydroxy, or C(O)NHR a ;

R 3 is hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 thioalkoxy, NH 2 , NHR b , or NR b R c ;

R 4 when taken together with R 4′ forms oxo, or R 4 when taken together with R 5 forms a double bond between the carbon and nitrogen atoms to which they are attached;

R 4′ when taken together with R 4 forms oxo, or is O − ;

R 5 is hydrogen, C 1 -C 4 alkyl, or when taken together with R 4 forms a double bond between the carbon and nitrogen atoms to which they are attached;

R 6 is hydrogen, halo, NH 2 , NHR b , or NR b R c ;

R 7 is an unshared electron pair, or C 1 -C 4 alkyl;

R 8 when taken together with R 9 forms a double bond between the carbon and nitrogen atoms to which they are attached, or R 8 when taken together with R 11 forms a double bond between the carbon and nitrogen atoms to which they are attached;

R 9 is hydrogen, C 1 -C 4 alkyl, or when taken together with R 8 forms a double bond between the carbon and nitrogen atoms to which they are attached;

R 10 is hydrogen or is absent;

R 11 is hydrogen, C 1 -C 4 alkyl, or when taken together with R 8 forms a double bond between the carbon and nitrogen atoms to which they are attached;

R 12 is hydrogen, formyl, or C 1 -C 4 alkyl optionally substituted with hydroxy or protected hydroxy;

R 13 and R 14 are each independently hydrogen or C 1 -C 4 alkyl;

R 15 is hydrogen, C 1 -C 4 alkyl, or (CH 2 ) n CH(R d )CH(NHR e )(COOR g );

R 16 is hydrogen or C 1 -C 4 alkyl;

R 17 is halo, NH 2 , NHR b , or NR b R c ;

R 18 is cyano, C(═NH)NH 2 , or CH 2 NH(R h );

R 19 is hydrogen, or C 1 -C 4 alkyl;

R 20 is:

(i) hydrogen;

(ii) hydroxy or protected hydroxy;

(iii) C 1 -C 4 alkoxy optionally substituted with COOR f ; or

(iv) C 1 -C 4 alkyl optionally substituted with hydroxy and/or COOR f , NH 2 , NHR m , or CONH 2 ;

R 21 is hydrogen, or when taken together with R 23 forms a double bond between the carbon atoms to which they are attached;

R 22 is hydrogen;

R 23 is hydrogen, or when taken together with R 21 forms a double bond between the carbon atoms to which they are attached;

R 24 and R 25 are each, independently, hydrogen or C 1 -C 4 alkyl;

R 26 is (CH 2 ) n CH(R d )CH(NHR e )(COOR g );

R 27 is C 1 -C 6 alkyl optionally substituted with cyano, or C 2 -C 6 alkenyl;

R 28 is C 1 -C 10 alkyl;

R 29 is a liquid or solid phase support reagent;

Q is N or CR 44 ;

Q′ is N or CR 45 ;

Q″ is N or CR 47 ;

Q′″ is N or CR 49 ;

Q iv is N or CR 50 ;

R 44 is hydrogen, halo, hydroxy, nitro, protected hydroxy, NH 2 , NHR b , or NR b R c , C 1 -C 6 alkyl, C 6 -C 10 aryl, C 6 -C 10 heteroaryl, C 3 -C 8 heterocyclyl, a ligand, a tethered ligand, or when taken together with R 45 forms —OCH 2 O—;

R 45 is hydrogen, halo, hydroxy, nitro, protected hydroxy, NH 2 , NHR b , or NR b R c , C 1 -C 6 alkyl, C 6 -C 10 aryl, C 6 -C 10 heteroaryl, C 3 -C 8 heterocyclyl, a ligand, a tethered ligand, or when taken together with R 44 or R 46 forms —OCH 2 O—;

R 46 is hydrogen, halo, hydroxy, nitro, protected hydroxy, NH 2 , NHR b , or NR b R c , C 1 -C 6 alkyl, C 6 -C 10 aryl, C 6 -C 10 heteroaryl, C 3 -C 8 heterocyclyl, a ligand, a tethered ligand, or when taken together with R 45 or R 47 forms —OCH 2 O—;

R 47 is hydrogen, halo, hydroxy, nitro, protected hydroxy, NH 2 , NHR b , or NR b R c , C 1 -C 6 alkyl, C 6 -C 10 aryl, C 6 -C 10 heteroaryl, C 3 -C 8 heterocyclyl, a ligand, a tethered ligand, or when taken together with R 46 or R 48 forms —OCH 2 O—;

R 48 is hydrogen, halo, hydroxy, nitro, protected hydroxy, NH 2 , NHR b , or NR b R c , C 1 -C 6 alkyl, C 6 -C 10 aryl, C 6 -C 10 heteroaryl, C 3 -C 8 heterocyclyl, a ligand, a tethered ligand, or when taken together with R 47 forms —OCH 2 O—;

R 49 R 50 , R 51 , R 52 , R 53 R 54 , R 57 , R 58 R 59 , R 60 , R 61 , R 62 , R 63 , R 64 , R 65 , R 66 , R 67 R 68 , R 69 R 70 , R 71 , and R 72 are each independently selected from hydrogen, halo, hydroxy, nitro, protected hydroxy, NH 2 , NHR b , or NR b R c , C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 6 -C 10 heteroaryl, C 3 -C 8 heterocyclyl, NC(O)R 17 , or NC(O)R o ;

R 55 is hydrogen, halo, hydroxy, nitro, protected hydroxy, NH 2 , NHR b , or NR b R c , C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 6 -C 10 heteroaryl, C 3 -C 8 heterocyclyl, NC(O)R 17 , or NC(O)R o , or when taken together with R 56 forms a fused aromatic ring which may be optionally substituted;

R 56 is hydrogen, halo, hydroxy, nitro, protected hydroxy, NH 2 , NHR b , or NR b R c , C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 6 -C 10 heteroaryl, C 3 -C 8 heterocyclyl, NC(O)R 17 , or NC(O)R o , or when taken together with R 55 forms a fused aromatic ring which may be optionally substituted;

X is O, S, or Se;

Y is O or S;

L is —C(O)(CH 2 ) q C(O)—, or —C(O)(CH 2 ) q S—;

Provided that R 1 , R 2 , and R 3 cannot all be hydrogen; further provided that when R 5 is hydrogen, R 6 cannot be NH 2 , NH(protecting group), or NH(iBu); further provided that when R 12 is hydrogen and R 8 and R 11 together form a double bond between the carbon and nitrogen atoms to which they are attached, R 9 and R 10 cannot both be hydrogen; further provided that when X and Y are O, R 19 is hydrogen, and R 21 and R 23 together form a double bond between the carbon atoms to which they are attached, R 20 cannot be hydrogen or CH 3 ;

R a is glycinyl, threonyl, or norvalyl, each of which may optionally be partially or fully protected;

R b is C 1 -C 6 alkyl or a nitrogen protecting group;

R c is C 1 -C 6 alkyl;

R d is hydrogen, hydroxy, protected hydroxy, or OOH;

R e is hydrogen, a nitrogen protecting group, or COOR 8 ;

R f is hydrogen, or C 1 -C 6 alkyl;

R g is C 1 -C 10 alkyl;

R h is hydrogen, or

R i and R j when taken together forms a double bond between the carbon atoms to which they are attached, or R i and R j when taken together form —O— between the carbon atoms to which they are attached;

R k and R l are each, independently, hydrogen, a hydroxylprotecting group, a sugar, or a fully or partially protected sugar;

R m is C 1 -C 4 alkyl optionally substituted with COOH;

R o is alkyl optionally substituted with halo, hydroxy, nitro, protected hydroxy, NH 2 , NHR b , or NR b R c , C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 6 -C 10 heteroaryl, C 3 -C 8 heterocyclyl, NC(O)R 17 , or NC(O)R o ;

n is 1-4; and

q is 0-4.

2 - 17 . (canceled)

18 . The monomer of claim 1 , wherein R 28 is isopropyl.

19 . The monomer of claim 1 , wherein X 5′ , X 5″ , and X 5′″ are any combination of the following formula:

20 . The compound of claim 1 , wherein X 5′ and X 5″ are siloxy and X 5′″ is cycloalkoxy.

21 . The monomer of claim 1 , wherein the orthoester protecting group has a formula (III):

22 . The monomer of claim 21 , wherein R 31 and R 32 are the same or different and are any combination of the following formulae:

wherein R 33 , R 34 , R 35 , R 36 , and R 37 is a compatible ligand, or hydrogen, or halogen, alkyl, or cyano substituent, and R 38 is compatible ligand.

23 . The monomer of claim 21 , wherein the orthoester is:

24 . The monomer of claim 1 , wherein R 29 is a fluoride-stable polystyrene based solid support or PEG.

25 - 40 . (canceled)

41 . The monomer of claim 1 , wherein B is selected from the group consisting of:

2-aminoadeninyl

2-methyladeninyl,

N6-methyladeninyl,

2-methylthio-N6-methyladeninyl,

N6-isopentenyladeninyl,

2-methylthio-N6-isopentenyladeninyl,

N6-(cis-hydroxyisopentenyl)adeninyl,

2-methylthio-N6-(cis-hydroxyisopentenyl)adeninyl,

N6-glycinylcarbamoyladeninyl,

N6-threonylcarbamoyladeninyl,

2-methylthio-N6-threonyl carbamoyladeninyl,

N6-methyl-N6-threonylcarbamoyladeninyl,

N6-hydroxynorvalylcarbamoyladeninyl,

2-methylthio-N6-hydroxynorvalyl carbamoyladeninyl,

N6,N6-dimethyladeninyl,

3-methylcytosinyl,

5-methylcytosinyl,

2-thiocytosinyl,

5-formylcytosinyl,

N4-methylcytosinyl,

5-hydroxymethylcytosinyl,

1-methylguaninyl,

N2-methylguaninyl,

7-methylguaninyl,

N2,N2-dimethylguaninyl,

N2,7-dimethylguaninyl,

N2,N2,7-trimethylguaninyl,

1-methylguaninyl,

7-cyano-7-deazaguaninyl,

7-aminomethyl-7-deazaguaninyl,

pseudouracilyl,

dihydrouracilyl,

5-methyluracilyl,

1-methylpseudouracilyl,

2-thiouracilyl,

4-thiouracilyl,

5-methyl-2-thiouracilyl,

3-(3-amino-3-carboxypropyl)uracilyl,

5-hydroxyuracilyl,

5-methoxyuracilyl,

uracilyl 5-oxyacetic acid,

uracilyl 5-oxyacetic acid methyl ester,

5-(carboxyhydroxymethyl)uracilyl,

5-(carboxyhydroxymethyl)uracilyl methyl ester,

5-methoxycarbonylmethyluracilyl,

5-methoxycarbonylmethyl-2-thiouracilyl,

5-aminomethyl-2-thiouracilyl,

5-methylaminomethyluracilyl,

5-methylaminomethyl-2-thiouracilyl,

5-methylaminomethyl-2-selenouracilyl,

5-carbamoylmethyluracilyl,

5-carboxymethylaminomethyluracilyl,

5-carboxymethylaminomethyl-2-thiouracilyl,

3-methyluracilyl,

1-methyl-3-(3-amino-3-carboxypropyl)pseudouracilyl,

5-carboxymethyluracilyl,

5-methyldihydrouracilyl,

3-methylpseudouracilyl,

42 . The monomer of claim 1 , wherein X 2 is —OC[OCH 2 CH 2 OC(O)CH 3 ] 2 ; R 27 is CH 3 ; R 28 is (CH 3 ) 2 CH—; X5′ and X5″ are trimethylsiloxy; X5′″ is cyclododecyloxy; and B is selected from the group consisting of:

2-aminoadeninyl,

2-methyladeninyl,

N6-methyladeninyl,

2-methylthio-N6-methyladeninyl,

N6-isopentenyladeninyl,

2-methylthio-N6-isopentenyladeninyl,

N6-(cis-hydroxyisopentenyl)adeninyl,

2-methylthio-N6-(cis-hydroxyisopentenyl)adeninyl,

N6-glycinylcarbamoyladeninyl,

N6-threonylcarbamoyladeninyl,

2-methylthio-N6-threonyl carbamoyladeninyl,

N6-methyl-N6-threonylcarbamoyladeninyl,

N6-hydroxynorvalylcarbamoyladeninyl,

2-methylthio-N6-hydroxynorvalyl carbamoyladeninyl,

N6,N6-dimethyladeninyl,

3-methylcytosinyl,

5-methylcytosinyl,

2-thiocytosinyl,

5-formylcytosinyl,

N4-methylcytosinyl,

5-hydroxymethylcytosinyl,

1-methylguaninyl,

N2-methylguaninyl,

7-methylguaninyl,

N2,N2-dimethylguaninyl,

N2,N2,7-trimethylguaninyl,

1-methylguaninyl,

7-cyano-7-deazaguaninyl,

7-aminomethyl-7-deazaguaninyl,

pseudouracilyl,

dihydrouracilyl,

5-methyluracilyl,

1-methylpseudouracilyl,

2-thiouracilyl,

4-thiouracilyl

5-methyl-2-thiouracilyl,

3-(3-amino-3-carboxypropyl)uracilyl,

5-hydroxyuracilyl,

5-methoxyuracilyl,

uracilyl 5-oxyacetic acid,

uracilyl 5-oxyacetic acid methyl ester,

5-(carboxyhydroxymethyl)uracilyl,

5-(carboxyhydroxymethyl)uracilyl methyl ester,

5-methoxycarbonylmethyluracilyl,

5-methoxycarbonylmethyl-2-thiouracilyl,

5-aminomethyl-2-thiouracilyl,

5-methylaminomethyluracilyl,

5-methylaminomethyl-2-thiouracilyl,

5-methylaminomethyl-2-selenouracilyl,

5-carbamoylmethyluracilyl,

5-carboxymethylaminomethyluracilyl,

5-carboxymethylaminomethyl-2-thiouracilyl,

3-methyluracilyl,

1-methyl-3-(3-amino-3-carboxypropyl) pseudouracilyl,

5-carboxymethyluracilyl,

5-methyldihydrouracilyl,

3-methylpseudouracilyl,

43 . The monomer of claim 1 , wherein X 2 is fluoro.

44 . The monomer of claim 1 , wherein B is:

45 . The monomer of claim 1 , wherein B is substituted or unsubstituted aryl attached to a tethered or untethered ligand.

46 . A protected monomer having a formula:

in which

u is 1 or 2; the wavy line represents a point of attachment for a ligand or a tethered ligand; and the dotted lines represent points of attachment for a first functionalized hydroxyl group; a second functionalized hydroxyl group; and an unfunctionalized hydroxyl group, a protected hydroxyl group, or hydrogen.

47 . The monomer of claim 46 , wherein the first functionalized hydroxyl group has the formula:

; in which

X 5′ , X 5″ , and X 5′″ include at least one alkoxy or siloxy substituent.

48 . The monomer of claim 46 , wherein the second functionalized hydroxyl group has one of the following formulas:

; in which

R 27 is C 1 -C 6 alkyl optionally substituted with cyano or C 2 -C 6 alkenyl; R 28 is C 1 -C 10 alkyl; • is a solid or liquid support reagent; and L is a linker.

49 . The monomer of claim 46 , wherein the ligand is a targeting group.

50 . The monomer of claim 49 , wherein the targeting group is a lipid, steroid, vitamin, carbohydrate, polyamine, amino acid, peptide, peptide mimetic or cleaving molecule.

51 . The monomer of claim 50 , wherein the steroid is cholesterol.

52 . The monomer of claim 46 , wherein the ligand is a diagnostic group.

53 . The monomer of claim 52 , wherein the diagnostic group is biotin, a fluorophore, an antibody or an antigen.

54 . The monomer of claim 46 , wherein the ligand has a formula (G)C(═H)NHR n , in which G is —O—, —NH—, or —CH 2 —; H is O or NH; and R n is H, C 1 -C 6 alkyl, C 6 -C 10 aryl, or C 5 -C 10 heteroaryl.

55 . The monomer of claim 46 , wherein the monomer has a tethered ligand.

56 . The monomer of claim 55 , wherein the ligand is tethered with a tether selected from the group consisting of: —C(O)—(CH 2 ) s —C(O)-(ligand); —C(O)—(CH 2 ) s —C(O)O-(ligand); —C(O)—O-(ligand); —C(O)—(CH 2 ) s —NH—; —C(O)—(CH 2 ) s —NH—C(O)-(ligand); —C(O)—(CH 2 ) s -(ligand); —C(O)—NH-(ligand); —C(O)-(ligand); —(CH 2 ) s —C(O)-(ligand); —(CH 2 ) s —C(O)O-(ligand); —(CH 2 ) s -(ligand); —(CH 2 ) s —NH—; and —(CH 2 ) s —NH—C(O)-(ligand), wherein s is 0-6.

57 . The monomer of claim 46 , wherein the monomer has the formula:

wherein, X 5′ , X 5″ , and X 5′″ include at least one alkoxy or siloxy substituent, ipr is an isopropyl group, and chol is a cholesterol radical.

58 . An iRNA agent having a monomer of claim 1 .

59 . A method of making an iRNA agent, the method comprising providing a first RNA sequence having a monomer of claim 1 and allowing the first RNA sequence to anneal to a complementary RNA sequence to form an iRNA agent.

60 . A method of synthesizing an iRNA agent, the method comprising incorporating a monomer of claim 1 into a first RNA sequence and allowing the first RNA sequence to anneal to a complementary RNA sequence to form an iRNA agent.