US 20140121152A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0121152 A1 Jenkins et al. (43) Pub. Date: May 1, 2014

(54) ACTIVE AGENT PRODRUGS WITH Publication Classification HETEROCYCLIC LINKERS (51) Int. C. C07K5/06 (2006.01) (75) Inventors: Thomas E. Jenkins, Half Moon Bay, A638/05 (2006.01) CA (US); Craig O. Husfeld, San Mateo, A6II 45/06 (2006.01) CA (US) C07K5/08 (2006.01) A638/06 (2006.01) (73) Assignee: Signature Therapeutics, Inc., Palo Alto, (52) U.S. C. CA (US) CPC. C07K5/06 (2013.01); C07K5/08 (2013.01); A6 IK38/06 (2013.01); A61K 45/06 (2013.01); (21) Appl. No.: 14/000,594 A6 IK38/05 (2013.01) USPC 514/1.3: 530/331:546/44; 546/226,544/361 (22) PCT Fled: Mar. 8, 2012 (57) ABSTRACT (86) PCT NO.: PCT/US12/28367 The embodiments provide prodrug compounds of Formulae S371 (c)(1), I-XVII. The present disclosure also provides compositions, (2), (4) Date: Dec. 27, 2013 and their methods of use, where the compositions comprise a prodrug compound of Formulae I-XVII that provides con trolled release of an active agent. Such compositions can Related U.S. Application Data optionally provide a trypsin inhibitor that interacts with the (60) Provisional application No. 61/451,019, filed on Mar. enzyme that mediates the controlled release of an active agent 9, 2011, provisional application No. 61/583,523, filed from the prodrug so as to attenuate enzymatic cleavage of the on Jan. 5, 2012. prodrug. Patent Application Publication May 1, 2014 Sheet 1 of 26 US 2014/O121152 A1

Figure 1

A. ---. x N srax °, w y . %. '. '.

thiitor Patent Application Publication May 1, 2014 Sheet 2 of 26 US 2014/O121152 A1

Figure 2

38ts

s

S.

SSS

Srs Patent Application Publication May 1, 2014 Sheet 3 of 26 US 2014/O121152 A1

Figure 2 (continued)

3S 8.

Patent Application Publication May 1, 2014 Sheet 4 of 26 US 2014/O121152 A1

Figure 3

Site, - &FES

fi & s s H H Fiss SSS $s ELS&S ISS &

PSE { R&FE:

s & ......

: s al s E. & & & s s 8 s *:::SF:SESS $3. Lists RSSS 8:S

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S

s I 8. ESSESSS SSSSSSSS: Patent Application Publication May 1, 2014 Sheet 5 of 26 US 2014/O121152 A1

Figure 4 -O OC from Oxycodone (28 umol/kg) -be OC from Compound KC-9 (31 umol/kg) - OC from Compound KC-11 (34 umol/kg) 1OO OC from Compound KC-12 (29 umol/kg) - OC from Compound KC-13 (29 umol/kg) -- OC from Compound KC-14 (29 umol/kg) -0. OC from Compound KC-15 (29 umol/kg) 10 -- OC from Compound KC-16 (29 umol/kg) - OC from Compound KC-17 (28 umol/kg) S o C g : 1 e x 9. O.1

O.O1

Time, hr Patent Application Publication May 1, 2014 Sheet 6 of 26 US 2014/O121152 A1

Figure 5A -A OC from Oxycodone (5.7 umol/kg) -0- OC from 20 mg OxyContin Tablet -e OC from Compound KC-12 (5.7 umol/kg) -H OC from Compound KC-13 (5.7umol/kg) -e OC from Compound KC-14 (5.7 umol/kg) OC from Compound KC-15 (5.7 umol/kg) as OC from Compound KC-16 (5.8 umol/kg) cHe OC from Compound KC-17 (5.8 umol/kg) - S 2 10

o o S 1 5

0.1

OO1

Time, hr

Figure 5B 1000 -o- OC from Compound KC-17 (5.8 umol/kg) -A OC from Oxycodone (5.7umol/kg) -0- OC from 20 mg OxyContin Tablet

-H OC from Compound KC-3 (5.7 umol/kg)

E o O s O ce g 9.

Time, hr Patent Application Publication May 1, 2014 Sheet 7 of 26 US 2014/O121152 A1

Figure 6A -o- OC from Compound KC-12 (6.5 pmol/kg) 1OO -H OC from Compound KC-12 (29 umol/kg)

- 10 S d 5 1 O ce X 9. O.1

0.01 O 6 12 18 24 Time, hr Figure 6B -o- OC from Compound KC-17 (6 umol/kg) 1OO -- OC from Compound KC-17 (28 umol/kg) -- OC from Compound KC-17 (60 umol/kg)

1O S O d 5 1 s O 9 e x O. O.1

O.O1 O 6 12 18 24 Time, hr Patent Application Publication May 1, 2014 Sheet 8 of 26 US 2014/O121152 A1

Figure 7A

-O OC from Compound KC-12 (6.5umol/kg) -H OC from Compound KC-12 ((6.5umol/kg) ) + Compound 109 (0.2 umol/kg) site OC from Compound KC-12 (6.5umol/kg) + Compound 109 (0.9 umol/kg) -0. OC from Compound KC-12 (6.5umol/kg)( ) + Compound 109 (1.9 umol/kg) 4.

S. d 5 2 "O O d 9.

24 Time, hr Figure 7B -O- OC from Compound KC-17 (6 umol/kg) -- OC from Compound KC-17 (6 umol/kg) + Compound 109 (0.2 umol/kg) -A- OC from Compound KC-17 (6 umol/kg) + Compound 109 (0.9 umol/kg)

-0. OC from Compound KC-17 (6 umol/kg) + Compound 109 (1.9 umol/kg) Patent Application Publication May 1, 2014 Sheet 9 of 26 US 2014/O121152 A1

Figure 7C -O- OC from Compound KC-17 (60 umol/kg) -H OC from Compound KC-17 (60 umol/kg) + Compound 109 (1.9 umol/kg) -- OC from Compound KC-17 (60 umol/kg) + Compound 109 (9.3 umol/kg) -0- OC from Compound KC-17 (60 umol/kg) + Compound 109 (18.5umol/kg)

40 23OO

1 O Patent Application Publication May 1, 2014 Sheet 10 of 26 US 2014/O121152 A1

Figure 8 -O Tapentadol from Compound TP-5 (34 umol/kg) H. Tapentadol from Compound TP-5 (34 umol/kg) + Compound 109 (55 umol/kg) 2.

O.

O 6 12 18 24 Time, hr Patent Application Publication May 1, 2014 Sheet 11 of 26 US 2014/O121152 A1

Figure 9

-- Hydrocodone from Compound KC-31 (28 umol/kg) 's. -o- Hydrocodone from Compound KC-31 (12 mol/kg) 's. -- Hydrocodone from Compound KC-31 (6 umol/kg) + Hydrocodone from HC (30 umol/kg)

-

8s 3 O) C 2 2

1 W - Y TN ------*..

O Nix O 1 2 3 4. 5 66 9 12 15 18 21 24 Time, hr Patent Application Publication May 1, 2014 Sheet 12 of 26 US 2014/O121152 A1

Figure 10 6 -O- Hydrocodone from HC (30 pmol/kg) -- Hydrocodone from Compound KC-32 (28 umol/kg)

-- Hydrocodone from Compound KC-35 (24 umol/kg) -- Hydrocodone from Compound KC-36 (27 umol/kg) . --- Hydrocodone from Compound KC-37 (28 umol/kg) 4.

3

O 2 4 6 8 Time, hr Patent Application Publication May 1, 2014 Sheet 13 of 26 US 2014/O121152 A1

Figure 11

-O- Hydrocodone from HC (30 umol/kg) -- Hydrocodone from Compound KC-38 (28 umol/kg) be Hydrocodone from Compound KC-39 (28 umol/kg)

Time, hr Patent Application Publication May 1, 2014 Sheet 14 of 26 US 2014/O121152 A1

Figure 12

6 -O- Hydrocodone from HC (30 pmol/kg) -H Hydrocodone from Compound KC-40 (28 umol/kg) 5 -- Hydrocodone from Compound KC-47 (28 umol/kg)

-X- Hydrocodone from Compound KC-50 (28 umol/kg)

Time, hr Patent Application Publication May 1, 2014 Sheet 15 of 26 US 2014/O121152 A1

Figure 13A

1O -o- Hydrocodone (HC) from Compound KC-40 (6 umol/kg) -th HC from Compound KC-40 (6 umol/kg) + Compound 109 (0.2 umol/kg) 8 be HC from Compound KC-40 (6 umol/kg) + Compound 109 (0.44 umol/kg) -- HC from Compound KC-40 (6 umol/kg) + Compound 109 (0.9mol/kg) d E 6 -- HC from Compound KC-40 (6 umol/kg) + Compound 109 (1.7 umol/kg)

Os d d 9 Os e E.

Time, hr Patent Application Publication May 1, 2014 Sheet 16 of 26 US 2014/O121152 A1

Figure 13B -- Hydrocodone from HC (30 umol/kg normalized to 65umol/kg) -- HC from Compound KC-40 (62 mol/kg) + Compound 109 (1.7 umol/kg) -)- HC from Compound KC-40 (62 mol/kg) + Compound 109 (4.4 umol/kg) -- HC from Compound KC-40 (62 umol/kg) + Compound 109 (9.0 umol/kg) -- HC from Compound KC-40 (62( mol/kg)) + Compound 109 (17.4( umol/kg)

Time, hr Patent Application Publication May 1, 2014 Sheet 17 of 26 US 2014/O121152 A1

Figure 13C

s Hydrocodone (HC) from Compound KC-50 (6 umol/kg) 12 es HC from Compound KC-50 (6 umol/kg) + Compound 109 0.2 Lmol/kg) a) HC from Compound KC-50 (6( umol/kg)) + Compound 109 0.44 umol/kg) es HC from Compound KC-50 (6 umol/kg ) + Compound 109 0.9 umol/kg) O -- HC from Compound KC-50 (6( umol/kg)) + Compound 109 1.7 umol/kg)

4.

Time, hr Patent Application Publication May 1, 2014 Sheet 18 of 26 US 2014/O121152 A1

Figure 13D Hydrocodone from HC (30pumol/kg normalized to 67 umol/kg)

12 HC from Compound KC-50 (64 umol/kg) + Compound 109 (1.7 umol/kg) HC from Compound KC-50 (64 umol/kg) + Compound 109 (4.4 umol/kg) HC from Compound KC-50 (64 umol/kg) + Compound 109 (9.0 umol/kg)

Time, hr Patent Application Publication May 1, 2014 Sheet 19 of 26 US 2014/O121152 A1

Figure 14A

80 -H Hydrocodone from HC (0.5umol/kg) -o-, HC from Compound KC-40 (0.1 umol/kg) -- HC from Compound KC-40 (0.5umol/kg) 60 --- HC from Compound KC-40 (2.0 umol/kg)

40 Patent Application Publication May 1, 2014 Sheet 20 of 26 US 2014/O121152 A1

Figure 14B

150 -- Hydrocodone from HC (0.5umol/kg) -o-, HC from Compound KC-40 (0.5umol/kg) + Compound 109 (0.14 umol/kg)

100

5 O

Figure 14C

150

-H Hydrocodone from HC (0.5umol/kg normalized to 2 umol/kg) -o-, HC from Compound KC-40 (2.0 umol/kg) + Compound 109 (0.56 umol/kg)

Time, hr Patent Application Publication May 1, 2014 Sheet 21 of 26 US 2014/O121152 A1

Figure 14D -H Hydrocodone from HC (0.5umol/kg normalized to 5umol/kg) 'T -- HC from Compound KC-40 (4.7amol/kg) + Compound 109 (14 amol/kg)

i

Time, hr Patent Application Publication May 1, 2014 Sheet 22 of 26 US 2014/O121152 A1

Figure 15A

H Hydrocodone from HC (0.5umol/kg) 60 -o-, HC from Compound KC-50 (0.1 umol/kg) -- HC from Compound KC-50 (0.5umol/kg) -be- HC from Compound KC-50 (2 umol/kg)

4O

20

Time, hr Patent Application Publication May 1, 2014 Sheet 23 of 26 US 2014/O121152 A1

Figure 15B

15 -H Hydrocodone from HC (0.5umol/kg) -o-, HC from Compound KC-50 (0.5 pmol/kg) - HC from Compound KC-50 (0.5 pmol/kg) + Compound 109 (0.14 umol/kg) -- HC from Compound KC-50 (0.5 pmol/kg) + Compound 109 (0.28 umol/kg) E o d O o

8C e E.

Time, hr Figure 15C -H Hydrocodone from HC (0.5umol/kg normalized to 5pmol/kg) 150 - HC from Compound KC-50 (5umol/kg) + Compound 109 (0.14 umol/kg) --- HC from Compound KC-50 (5umol/kg) + Compound 109 (0.7 umol/kg)

100

50

Time, hr Patent Application Publication May 1, 2014 Sheet 24 of 26 US 2014/O121152 A1

Figure 16 -H Oxycodone from OC (28 umol/kg) 16 -- OC from Compound KC-55 (6 umol/kg) W -o- OC from Compound KC-55 (28 umol/kg) V

Time, hr Patent Application Publication May 1, 2014 Sheet 25 of 26 US 2014/O121152 A1

Figure 17A

20 -O OC from Compound KC-55 (6 umol/kg) -H OC from Compound KC-55 (6 umol/kg) + Compound 109 (0.9 p.mol/kg)

15

10 Patent Application Publication May 1, 2014 Sheet 26 of 26 US 2014/O121152 A1

Figure 17B H. Oxycodone (28 umol/kg nomalized to 36 umol/kg) -o- OC from Compound KC-55 (36 umol/kg) + Compound 109 (5umol/kg)

20

15

10

Time, hr US 2014/O121 152 A1 May 1, 2014

ACTIVE AGENT PRODRUGS WITH hydroxyl group of the enolic tautomer of the ketone is HETEROCYCLIC LINKERS replaced by a covalent bond to —C(O) NI (A ring)-Y— (CRR). NH CO) CH(R) N(R) C(O) CH CROSS REFERENCE TO RELATED (R) N(R) R': a residue of a phenolic active agent, APPLICATIONS wherein the hydrogenatom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O) N(A ring)-Y- 0001. This application claims the benefit of U.S. Provi (CRR). NH CO) CH(R) N(R) C(O) CH sional Application No. 61/451,019 filed Mar. 9, 2011 and (R) N(R) R', and a residue of an amide-containing U.S. Provisional Application No. 61/583,523 filed Jan. 5, active agent, wherein —C(O) N(A ring)-Y—(CRR) 2012, which are hereby incorporated by reference in their NH C(O) CH(R) N(R) C(O) CH(R) N entireties. (R) R' is connected to the amide-containing active agent INTRODUCTION through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer, 0002. A number of drugs are susceptible to misuse, abuse, or overdose. Use of and access to these drugs therefore needs O008) the A ring is a heterocyclic 5 to 12-membered ring; to be controlled. The control of access to the drugs is expen 0009 each Y is independently selected from alkyl, substi sive to administer and can result in denial of treatment for tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted patients that are notable to present themselves for dosing. For alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car example, patients suffering from acute pain may be denied boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa treatment with a drug unless they have been admitted to a cyl. Substituted aminoacyl, amino, Substituted amino, acy hospital. Furthermore, control of use is often ineffective, lamino, Substituted acylamino, and cyano; leading to Substantial morbidity and deleterious Social con 0010 c is a number from Zero to 3: Sequences. 10011 each R" is independently selected from hydrogen, alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, SUMMARY substituted alkynyl, aryl, substituted aryl, acyl, substituted 0003. This disclosure concerns a prodrug of an active acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, agent that provides controlled release of the active agent. aminoacyl, Substituted aminoacyl, amino, Substituted amino, Such a prodrug comprises an active agent covalently attached acylamino, Substituted acylamino, and cyano; to a promoiety. The promoiety comprises an enzyme-cleav 0012 each R is independently selected from hydrogen, able moiety and a cyclizable spacer leaving group Such that alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, the active agent prodrug provides controlled release of the substituted alkynyl, aryl, substituted aryl, acyl, substituted active agent via enzyme cleavage followed by intramolecular acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, cyclization. The enzyme-mediated release of the active agent aminoacyl, Substituted aminoacyl, amino, Substituted amino, can occur in the gastrointestinal tract upon oral administra acylamino, Substituted acylamino, and cyano; or tion of the corresponding prodrug. Thus, prodrugs of the disclosure provide efficient delivery of active agent when (0013 R' and R together with the carbon to which they are ingested. attached can form a cycloalkyl or Substituted cycloalkyl 0004. The present disclosure also provides a composition, group, or two R' or R groups on adjacent carbon atoms, Such as a pharmaceutical composition, that comprises an together with the carbonatoms to which they are attached, can active agent prodrug of the embodiments. Such a composition form a cycloalkyl or Substituted cycloalkyl group; can optionally provide an inhibitor that interacts with the 0014) a is an integer from one to 8: enzyme that mediates the controlled release of active agent 00.15 provided that when a is one, the A ring is a hetero from the prodrug so as to attenuate enzymatic cleavage of the cyclic 6 to 12-membered ring; and when the A ring is a prodrug. The disclosure provides for the enzyme being a heterocyclic 5-membered ring, then a is an integer from 2 to gastrointestinal (GI) enzyme. Such as trypsin. Also provided 8: are methods of use, Such as a method of providing patients with controlled release of active agent using an active agent 10016 each R is independently hydrogen, alkyl, substi prodrug of the embodiments. tuted alkyl, aryl or substituted aryl; 0005. The embodiments include an active agent prodrug I0017 R is selected from hydrogen, alkyl, substituted that is a compound of formula I alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl: (I) I0018 each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, sub O R1 R2 O R3 R6 stituted arylalkyl, heteroalkyl, substituted heteroalkyl, het l, M. N R 7 eroaryl, substituted heteroaryl, heteroarylalkyl, and substi X N N N tuted heteroarylalkyl: A 5 H R O RJ, 0019 b is a number from Zero to 100; and (Y), (0020) R' is selected from hydrogen, alkyl, substituted alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted 0006 wherein alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi 0007 X is selected from a residue of a ketone-containing tuted arylalkyl: active agent, wherein the hydrogenatom of the corresponding 0021 or a salt, hydrate or solvate thereof. US 2014/O121 152 A1 May 1, 2014

0022. The embodiments include an opioid prodrug that is heteroalkyl, substituted heteroalkyl, heteroaryl, substituted a compound of formula II: heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl: I0035 each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, sub (II) stituted arylalkyl, heteroalkyl, substituted heteroalkyl, het eroaryl, substituted heteroaryl, heteroarylalkyl, and substi l R1 R2 O R3 R6 7 tuted heteroarylalkyl: X N N R N N 0036 b is a number from Zero to 100; and A 5 I0037 R’ is selected from hydrogen, alkyl, substituted H R O RJ, alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted (Y), alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi tuted arylalkyl: 0023 wherein 0038 or a salt, hydrate or solvate thereof. 0024 X is selected from a residue of a ketone-containing 0039. Certain embodiments provide controlled release of opioid, wherein the hydrogen atom of the corresponding ketone-containing active agent. More particularly, the hydroxyl group of the enolic tautomer of the ketone is embodiments relate to a prodrug of a ketone-containing replaced by a covalent bond to —C(O)—N(A ring)-Y— active agent that provides controlled release of the active (CRR). NH CO) CH(R) N(R) C(O) CH agent. Such a prodrug comprises a ketone-containing active (R) N(R) R': a residue of a phenolic opioid, wherein agent covalently attached to a promoiety through the enolic the hydrogenatom of the phenolic hydroxyl group is replaced oxygen atom of the ketone-containing active agent. The pro by a covalent bond to —C(O) N(A ring)-Y. (CRR) moiety comprises an enzyme-cleavable moiety and a cycliz NH C(O) CH(R) N(R) C(O) CH(R) N able spacer leaving group Such that the ketone-modified (R) R', and a residue of an amide-containing opioid, active agent prodrug provides controlled release of active wherein - C(O) N(A ring)-Y-(CRR). NH C agent via enzyme cleavage followed by intramolecular (O) CH(R) N(R) C(O) CH(R) N(R) R7 is cyclization. Ketone-modified active agent prodrugs of the connected to the amide-containing opioid through the oxygen disclosure provide efficient delivery of active agent when of the amide group, wherein the amide group is converted to ingested. The present disclosure also provides a composition, an amide enol or an imine tautomer, Such as a pharmaceutical composition, that comprises a 0025 the A ring is a heterocyclic 5 to 12-membered ring: ketone-modified active agent prodrug of the embodiments. 0026 each Y is independently selected from alkyl, substi Also provided are methods of use, such as a method of pro tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted viding patients with controlled release of ketone-containing alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car active agent using a ketone-modified active agent prodrug of boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa the embodiments. cyl. Substituted aminoacyl, amino, Substituted amino, acy lamino, Substituted acylamino, and cyano; 0040. The embodiments include a ketone-modified active 0027 c is a number from Zero to 3: agent prodrug that is a compound of formula IIIa: 0028 each R" is independently selected from hydrogen, alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted (IIIa) acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, O R1 R2 O R3 R6 aminoacyl, Substituted aminoacyl, amino, Substituted amino, acylamino, Substituted acylamino, and cyano; l N R7 I0029 each R is independently selected from hydrogen, X N NN N alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, A 5 substituted alkynyl, aryl, substituted aryl, acyl, substituted H R O R3 acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, (Y), aminoacyl, Substituted aminoacyl, amino, Substituted amino, acylamino, Substituted acylamino, and cyano; or 0041 wherein 0030) R' and R together with the carbon to which they are attached can form a cycloalkyl or Substituted cycloalkyl 0042 X represents a residue of a ketone-containing active group, or two R' or R groups on adjacent carbon atoms, agent, wherein the hydrogen atom of the corresponding together with the carbonatoms to which they are attached, can hydroxyl group of the enolic tautomer of the ketone is form a cycloalkyl or Substituted cycloalkyl group; replaced by a covalent bond to —C(O) NI (A ring)-Y— 0031 a is an integer from one to 8: (CRR). NH CO) CH(R) N(R) C(O) CH 0032 provided that when a is one, the A ring is a hetero (R) N(R) R7: cyclic 6 to 12-membered ring; and when the A ring is a 0043 the A ring is a heterocyclic 5 to 12-membered ring; heterocyclic 5-membered ring, then a is an integer from 2 to 0044 each Y is independently selected from alkyl, substi 8: tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted I0033 each R is independently hydrogen, alkyl, substi alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car tuted alkyl, aryl or substituted aryl; boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa 0034 R is selected from hydrogen, alkyl, substituted cyl. Substituted aminoacyl, amino, Substituted amino, acy alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, lamino, Substituted acylamino, and cyano; US 2014/O121 152 A1 May 1, 2014

0045 c is a number from Zero to 3: 0058. The embodiments include a phenolic active agent I0046) each R" is independently selected from hydrogen, prodrug that is a compound of formula VIIa: alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, (VIIa) aminoacyl, Substituted aminoacyl, amino, Substituted amino, O R1 R2 O R3 R6 acylamino, Substituted acylamino, and cyano; - -4 N R 7 I0047 each R is independently selected from hydrogen, N N alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, A 5 substituted alkynyl, aryl, substituted aryl, acyl, substituted H R O R3 acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, (Y), aminoacyl, Substituted aminoacyl, amino, Substituted amino, 0059 wherein acylamino, Substituted acylamino, and cyano; or 0060 X represents a residue of a phenolic active agent, 0048 RandR together with the carbon to which they are wherein the hydrogenatom of the phenolic hydroxyl group is attached can form a cycloalkyl or Substituted cycloalkyl replaced by a covalent bond to —C(O) NI (A ring)-Y— group, or two R' or R groups on adjacent carbon atoms, (CRR). NH C(O)-CH(R) N(R)-C(O)-CH together with the carbonatoms to which they are attached, can (R) N(R) R': form a cycloalkyl or Substituted cycloalkyl group; 0061 the A ring is a heterocyclic 5 to 12-membered ring: 0062 each Y is independently selected from alkyl, substi 0049 a is an integer from one to 8: tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car 0050 provided that when a is one, the A ring is a hetero boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa cyclic 6 to 12-membered ring; and when the A ring is a cyl. Substituted aminoacyl, amino, Substituted amino, acy heterocyclic 5-membered ring, then a is an integer from 2 to lamino, Substituted acylamino, and cyano; 8: 0063 c is a number from Zero to 3: 0051 each R is independently hydrogen, alkyl, substi I0064 each R" is independently selected from hydrogen, tuted alkyl, aryl or substituted aryl; alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, Substituted alkynyl, aryl, Substituted aryl, acyl, substituted 0052 R is selected from hydrogen, alkyl, substituted acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aminoacyl, Substituted aminoacyl, amino, Substituted amino, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted acylamino, Substituted acylamino, and cyano; heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl: I0065 each R is independently selected from hydrogen, alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, I0053 each R is independently selected from hydrogen, substituted alkynyl, aryl, substituted aryl, acyl, substituted alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, sub acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, stituted arylalkyl, heteroalkyl, substituted heteroalkyl, het aminoacyl, Substituted aminoacyl, amino, Substituted amino, eroaryl, substituted heteroaryl, heteroarylalkyl, and substi acylamino, Substituted acylamino, and cyano; or tuted heteroarylalkyl: I0066) R' and R together with the carbon to which they are attached can form a cycloalkyl or Substituted cycloalkyl 0054 b is a number from Zero to 100; and group, or two R' or R groups on adjacent carbon atoms, I0055) R' is selected from hydrogen, alkyl, substituted together with the carbonatoms to which they are attached, can alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted form a cycloalkyl or Substituted cycloalkyl group; alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi 0067 a is an integer from one to 8: tuted arylalkyl: 0068 provided that when a is one, the A ring is a hetero cyclic 6 to 12-membered ring; and when the A ring is a 0056 or a salt, hydrate or solvate thereof. heterocyclic 5-membered ring, then a is an integer from 2 to 0057 Certain embodiments provide controlled release of 8: phenolic active agents. More particularly, the embodiments I0069 each R is independently hydrogen, alkyl, substi relate to a prodrug of a phenolic active agent that provides tuted alkyl, aryl or substituted aryl; controlled release of the active agent. Such a prodrug com 10070 R is selected from hydrogen, alkyl, substituted prises a phenolic active agent covalently attached to a pro alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, moiety through the phenolic oxygen atom of the phenolic heteroalkyl, substituted heteroalkyl, heteroaryl, substituted active agent. The promoiety comprises an enzyme-cleavable heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl: moiety and a cyclizable spacer leaving group Such that the (0071) each R is independently selected from hydrogen, phenolic active agent prodrug provides controlled release of alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, sub active agent via enzyme cleavage followed by intramolecular stituted arylalkyl, heteroalkyl, substituted heteroalkyl, het cyclization. Phenolic active agent prodrugs of the disclosure eroaryl, substituted heteroaryl, heteroarylalkyl, and substi provide efficient delivery of active agent when ingested. The tuted heteroarylalkyl: present disclosure also provides a composition, such as a 0072 b is a number from Zero to 100: pharmaceutical composition, that comprises a phenolic active I0073 R’ is selected from hydrogen, alkyl, substituted agent prodrug of the embodiments. Also provided are meth alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted ods of use, Such as a method of providing patients with alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi controlled release of phenolic active agent using a phenolic tuted arylalkyl: active agent prodrug of the embodiments. 0074 or a salt, hydrate or solvate thereof. US 2014/O121 152 A1 May 1, 2014

0075 Certain embodiments provide controlled release of together with the carbonatoms to which they are attached, can amide-containing active agents. More particularly, the form a cycloalkyl or Substituted cycloalkyl group; embodiments relate to a prodrug of an amide-containing I0085 a is an integer from one to 8: active agent that provides controlled release of the active I0086 provided that when a is one, the A ring is a hetero agent. Such a prodrug comprises an amide-containing active cyclic 6 to 12-membered ring; and when the A ring is a agent covalently attached to a promoiety through the enolic heterocyclic 5-membered ring, then a is an integer from 2 to oxygenatom of the amide enol moiety or through the oxygen 8: of the imine tautomer of the amide-containing active agent. I0087 each R is independently hydrogen, alkyl, substi The promoiety comprises an enzyme-cleavable moiety and a tuted alkyl, aryl or substituted aryl; cyclizable spacer leaving group Such that the amide-modified I0088 R is selected from hydrogen, alkyl, substituted active agent prodrug provides controlled release of active alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, agent via enzyme cleavage followed by intramolecular heteroalkyl, substituted heteroalkyl, heteroaryl, substituted cyclization. Amide-modified active agent prodrugs of the dis heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl: closure provide efficient delivery of active agent when ingested. The present disclosure also provides a composition, I0089 each R is independently selected from hydrogen, Such as a pharmaceutical composition, that comprises an alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, sub amide-modified active agent prodrug of the embodiments. stituted arylalkyl, heteroalkyl, substituted heteroalkyl, het Also provided are methods of use, such as a method of pro eroaryl, substituted heteroaryl, heteroarylalkyl, and substi viding patients with controlled release of amide-containing tuted heteroarylalkyl: active agent using an amide-modified active agent prodrug of 0090 b is a number from Zero to 100: the embodiments. I0091) R' is selected from hydrogen, alkyl, substituted alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted 0076. The embodiments include an amide containing alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi active agent prodrug that is a compound of formula XIa: tuted arylalkyl: 0092 or a salt, hydrate or solvate thereof. (XIa) 0093 Certain embodiments provide controlled release of acetaminophen. More particularly, the embodiments relate to O R R2 O R3 R6 a prodrug of acetaminophen that provides controlled release -l N R7 of acetaminophen. Such a prodrug comprises acetaminophen X N covalently attached to a promoiety through the phenolic oxy A gen atom of acetaminophen or through the oxygen of the H R O R3 amide group of acetaminophen. The promoiety comprises an (Y), enzyme-cleavable moiety and a cyclizable spacer leaving group Such that the acetaminophen prodrug provides con 0.077 wherein trolled release of acetaminophen via enzyme cleavage fol 0078 X represents a residue of an amide-containing active lowed by intramolecular cyclization. Acetaminophen pro agent, wherein –C(O) N (A ring)-Y. (CRR), drugs of the disclosure provide efficient delivery of NH C(O) CH(R) N(R) C(O) CH(R) N(R) acetaminophen when ingested. The present disclosure also R is connected to the amide-containing active agent provides a composition, such as a pharmaceutical composi through the oxygen of the amide group, wherein the amide tion, that comprises acetaminophen prodrug of the embodi group is converted to an amide enol or an imine tautomer, ments. Also provided are methods of use. Such as a method of 0079 the A ring is a heterocyclic 5 to 12-membered ring: providing patients with controlled release of acetaminophen 0080 each Y is independently selected from alkyl, substi using acetaminophen prodrug of the embodiments. tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted 0094. The embodiments include an acetaminophen pro alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car drug that is a compound of formula XIV: boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa cyl. Substituted aminoacyl, amino, Substituted amino, acy lamino, Substituted acylamino, and cyano; (XIV) 0081 c is a number from Zero to 3: O R1 R2 O R3 R6 I0082 each R" is independently selected from hydrogen, ls N R7 alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, X N N substituted alkynyl, aryl, substituted aryl, acyl, substituted A acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, H R5 O RJ, aminoacyl, Substituted aminoacyl, amino, Substituted amino, acylamino, Substituted acylamino, and cyano; (Y), I0083) each R is independently selected from hydrogen, alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, 0.095 wherein substituted alkynyl, aryl, substituted aryl, acyl, substituted 0096 X represents acetaminophen, wherein the hydrogen acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, atom of the phenolic hydroxyl group of acetaminophen is aminoacyl, Substituted aminoacyl, amino, Substituted amino, replaced by a covalent bond to —C(O) N(A ring)-Y- acylamino, Substituted acylamino, and cyano; or (CRR). NH CO) CH(R) N(R) C(O) CH I0084) R' and R together with the carbon to which they are (R) N(R) R' or wherein—C(O) N (A ring)-Y)— attached can form a cycloalkyl or Substituted cycloalkyl (CRR). NH CO) CH(R) N(R) C(O) CH group, or two R' or R groups on adjacent carbon atoms, (R) N(R) R' is connected to acetaminophen through US 2014/O121 152 A1 May 1, 2014 the oxygen of the amide group of acetaminophen, wherein the ingestion of prodrug with inhibitor (dashed line) where drug amide group is converted to an amide enol or an imine tau Cmax and drug Tmax are modified relative to that of prodrug tomer, without inhibitor (solid line). Panel C is a schematic of a PK 0097 the A ring is a heterocyclic 5 to 12-membered ring: profile following ingestion of prodrug with inhibitor (dashed 0098 each Y is independently selected from alkyl, substi line) where drug Tmax is modified relative to that of prodrug tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted without inhibitor (solid line). alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car 0113 FIG.3 provides schematics representing differential boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa concentration-dose PK profiles that can result from the dos cyl. Substituted aminoacyl, amino, Substituted amino, acy ing of multiples of a dose unit (X axis) of the present disclo lamino, Substituted acylamino, and cyano; sure. Different PK profiles (as exemplified herein for a rep 0099 c is a number from Zero to 3: resentative PK parameter, drug Cmax (Y axis)) can be I0100 each R" is independently selected from hydrogen, provided by adjusting the relative amount of prodrug and GI alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, enzyme inhibitor contained in a single dose unit or by using a substituted alkynyl, aryl, substituted aryl, acyl, substituted different prodrug or inhibitor in the dose unit. acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoacyl, Substituted aminoacyl, amino, Substituted amino, 0114 FIG. 4 compares mean plasma concentrations over acylamino, Substituted acylamino, and cyano; time of oxycodone release following PO administration to 0101 each R is independently selected from hydrogen, rats of several ketone-modified active agent prodrugs of the alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, embodiments. substituted alkynyl, aryl, substituted aryl, acyl, substituted 0115 FIG. 5A compares mean plasma concentrations acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, over time of oxycodone release following PO administration aminoacyl, Substituted aminoacyl, amino, Substituted amino, to dogs of several ketone-modified active agent prodrugs of acylamino, Substituted acylamino, and cyano; or the embodiments. FIG. 5B compares mean plasma concen I0102) R' and R together with the carbon to which they are trations over time of oxycodone release following PO admin attached can form a cycloalkyl or Substituted cycloalkyl istration to dogs of ketone-modified active agent prodrug group, or two R' or R groups on adjacent carbon atoms, Compound KC-17 of the embodiments, oxycodone prodrug together with the carbonatoms to which they are attached, can Compound KC-3, OxyContin R tablets, or oxycodone HC1. form a cycloalkyl or Substituted cycloalkyl group; 0116 FIG. 6A compares mean plasma concentrations 0103 a is an integer from one to 8: over time of oxycodone release following PO administration 0104 provided that when a is one, the A ring is a hetero to rats of increasing doses of ketone-modified active agent cyclic 6 to 12-membered ring; and when the A ring is a prodrug Compound KC-12. FIG. 6B compares mean plasma heterocyclic 5-membered ring, then a is an integer from 2 to concentrations over time of oxycodone release following PO 8: administration to rats of increasing doses of ketone-modified I0105 each R is independently hydrogen, alkyl, substi active agent prodrug Compound KC-17. tuted alkyl, aryl or substituted aryl; 0117 FIG. 7A compares mean plasma concentrations I0106 R is selected from hydrogen, alkyl, substituted over time of oxycodone release following PO administration alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, to rats of ketone-modified active agent prodrug Compound heteroalkyl, substituted heteroalkyl, heteroaryl, substituted KC-12 co-dosed with increasing amounts of trypsin inhibitor heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl: Compound 109. FIG. 7B and FIG.7C compare mean plasma I0107 each R is independently selected from hydrogen, concentrations over time of oxycodone release following PO alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, sub administration to rats of two doses of ketone-modified active stituted arylalkyl, heteroalkyl, substituted heteroalkyl, het agent prodrug Compound KC-17, each co-dosed with eroaryl, substituted heteroaryl, heteroarylalkyl, and substi increasing amounts of trypsin inhibitor Compound 109. tuted heteroarylalkyl: 0108 b is a number from Zero to 100: 0118 FIG. 8 compares mean plasma concentrations over 0109 R7 is selected from hydrogen, alkyl, substituted time of tapentadol release following PO administration to rats alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted of phenolic active agent prodrug Compound TP-5 in the alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi absence or presence of a co-dose of trypsin inhibitor Com tuted arylalkyl: pound 109. 0110 or a salt, hydrate or solvate thereof. 0119 FIG. 9 compares mean plasma concentrations over time of hydrocodone release following PO administration to BRIEF DESCRIPTION OF THE FIGURES rats of increasing doses of ketone-modified active agent pro drug Compound KC-31. 0111 FIG. 1 is a schematic representing the effect of increasing the level of a GI enzyme inhibitor (“inhibitor', X I0120 FIG. 10 compares mean plasma concentrations over axis) on a PK parameter (e.g., drug Cmax) (Yaxis) for a fixed time of hydrocodone release following PO administration to dose of prodrug. The effect of inhibitor upon a prodrug PK rats of hydrocodone and PO administration to rats of hydro parameter can range from undetectable, to moderate, to com codone prodrugs Compound KC-32, Compound KC-35, plete inhibition (i.e., no detectable drug release). Compound KC-36, and Compound KC-37. 0112 FIG. 2 provides schematics of drug concentration in I0121 FIG. 11 compares mean plasma concentrations over plasma (Yaxis) over time (X axis). Panel A is a schematic of time of hydrocodone release following PO administration to a pharmacokinetic (PK) profile following ingestion of pro rats of hydrocodone and PO administration to rats of hydro drug with a GI enzyme inhibitor (dashed line) where the drug codone prodrugs Compound KC-38 and Compound KC-39. Cmax is modified relative to that of prodrug without inhibitor 0.122 FIG. 12 compares mean plasma concentrations over (solid line). Panel B is a schematic of a PK profile following time of hydrocodone release following PO administration to US 2014/O121 152 A1 May 1, 2014

rats of hydrocodone and PO administration to rats of hydro propan-2-yl. In some embodiments, an alkyl group comprises codone prodrugs Compound KC-40, Compound KC-47, and from 1 to 20 carbon atoms. In other embodiments, an alkyl Compound KC-50. group comprises from 1 to 10 carbon atoms. In still other 0123 FIG. 13A compares mean plasma concentrations embodiments, an alkyl group comprises from 1 to 6 carbon over time of hydrocodone release following PO administra atoms, such as from 1 to 4 carbon atoms. tion to rats of prodrug Compound KC-40 with increasing 0.130 Alkanyl by itself or as part of another substituent amounts of co-dosed trypsin inhibitor Compound 109. FIG. refers to a saturated branched, straight-chain or cyclic alkyl 13B compares mean plasma concentrations over time of radical derived by the removal of one hydrogen atom from a hydrocodone release following PO administration to rats of single carbon atom of an alkane. Typical alkanyl groups prodrug Compound KC-40 with increasing amounts of co include, but are not limited to, methanyl; ethanyl; propanyls dosed trypsin inhibitor Compound 109 to hydrocodone val Such as propan-1-yl, propan-2-yl (isopropyl), cyclopropan-1- ues expected from a normalized hydrocodone dose. FIG. 13C yl, etc.; butanyls such as butan-1-yl, butan-2-yl (sec-butyl), compares the mean plasma concentrations over time of 2-methyl-propan-1-yl (isobutyl), 2-methyl-propan-2-yl hydrocodone release following PO administration to rats of (t-butyl), cyclobutan-1-yl, etc.; and the like. prodrug Compound KC-50 with increasing amounts of co dosed trypsin inhibitor Compound 109. FIG. 13D compares I0131 “Alkylene' refers to a branched or unbranched satu mean plasma concentrations over time of hydrocodone rated hydrocarbon chain, usually having from 1 to 40 carbon release following PO administration to rats of prodrug Com atoms, more usually 1 to 10 carbon atoms and even more pound KC-50 with increasing amounts of co-dosed trypsin usually 1 to 6 carbon atoms. This term is exemplified by inhibitor Compound 109 to hydrocodone values expected groups such as methylene (—CH2—), ethylene from a normalized hydrocodone dose. (—CHCH ), the propylene isomers (e.g., 0124 FIG. 14A compares mean plasma concentrations —CH2CH2CH2— and —CH(CH)CH ) and the like. over time of hydrocodone following PO administration to I0132 Alkenyl' by itself or as part of another substituent dogs of hydrocodone and PO administration to dogs of refers to an unsaturated branched, straight-chain or cyclic increasing amounts of prodrug Compound KC-40. FIG. 14B, alkyl radical having at least one carbon-carbon double bond FIGS. 14C and 14D each compares mean plasma concentra derived by the removal of one hydrogen atom from a single tions over time of hydrocodone following PO administration carbon atom of an alkene. The group may be in either the cis to dogs of respectively, 1, 4 or 10 dose units comprising or trans conformation about the double bond(s). Typical alk prodrug Compound KC-40 and trypsin inhibitor Compound enyl groups include, but are not limited to, ethenyl; propenyls 109 to plasma concentrations of hydrocodone following PO such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (al administered to dogs of 1 dose equivalent of hydrocodone or lyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1- predicted concentrations for 4 or 10 dose equivalents of yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl hydrocodone, respectively. prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, 0.125 FIG. 15A compares mean plasma concentrations buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, over time of hydrocodone following PO administration to cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the dogs of hydrocodone and PO administration to dogs of like. increasing amounts of prodrug Compound KC-50. FIG. 15B 0.133 "Alkynyl' by itself or as part of another substituent and FIG.15C compare mean plasma concentrations overtime refers to an unsaturated branched, straight-chain or cyclic of hydrocodone following PO administration to dogs of alkyl radical having at least one carbon-carbon triple bond hydrocodone to plasma concentrations over time of hydroc derived by the removal of one hydrogen atom from a single odone following PO administration to dogs of the indicated carbonatom of an alkyne. Typical alkynyl groups include, but doses of prodrug Compound KC-50 with or without trypsin are not limited to, ethynyl; propynyls such as prop-1-yn-1-yl, inhibitor Compound 109. prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl, but-1- 0126 FIG. 16 compares mean plasma concentrations over yn-3-yl, but-3-yn-1-yl, etc.; and the like. time of oxycodone release following PO administration to I0134. Acyl' by itself or as part of another substituent rats of oxycodone prodrug Compound KC-55 or oxycodone. refers to a radical C(O)R', where R' is hydrogen, alkyl, 0127 FIG. 17A provides oxycodone exposure results for cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, het rats orally administered prodrug Compound KC-55 alone or eroaryl, heteroarylalkyl as defined herein and substituted ver co-dosed with trypsin inhibitor Compound 109. FIG. 17B sions thereof. Representative examples include, but are not provides oxycodone exposure results for rats orally adminis limited to formyl, acetyl, cyclohexylcarbonyl, cyclohexylm tered prodrug Compound KC-55 alone or co-dosed with ethylcarbonyl, benzoyl, benzylcarbonyl, piperonyl, Succinyl, trypsin inhibitor Compound 109. and malonyl, and the like. I0135 “Acylamino” refers to the groups - NRC(O) TERMS alkyl, - NRC(O) substituted alkyl, NRC(O)cycloalkyl, 0128. The following terms have the following meaning - NRC(O) substituted cycloalkyl, - NRC(O)cycloalk unless otherwise indicated. Any undefined terms have their enyl, substituted cycloalkenyl, - NRC(O)alkenyl, art recognized meanings. - NRC(O) substituted alkenyl, - NRC(O)alkynyl, 0129. Alkyl by itself or as part of another substituent - NRC(O) substituted alkynyl, - NRC(O)aryl, refers to a saturated branched or straight-chain monovalent - NRC(O) substituted aryl, - NRC(O)heteroaryl, hydrocarbon radical derived by the removal of one hydrogen - NRC(O) substituted heteroaryl, - NRC(O)heterocy atom from a single carbon atom of a parent alkane. Typical clic, and NRC(O) substituted heterocyclic, wherein R' alkyl groups include, but are not limited to, methyl, ethyl, is hydrogen or alkyl and wherein alkyl, Substituted alkyl, propyls such as propan-1-yl or propan-2-yl; and butyls. Such alkenyl, Substituted alkenyl, alkynyl. Substituted alkynyl, as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl or 2-methyl cycloalkyl, Substituted cycloalkyl, cycloalkenyl, Substituted US 2014/O121 152 A1 May 1, 2014

cycloalkenyl, aryl. Substituted aryl, heteroaryl, Substituted moiety is (C-C). In certain embodiments, an arylalkyl heteroaryl, heterocyclic, and Substituted heterocyclic are as group is (C7-Co) arylalkyl, e.g., the alkanyl, alkenyl or alky defined herein. nyl moiety of the arylalkyl group is (C-Cs) and the aryl I0136 “Amino” refers to the group - NH. moiety is (C-C). 0137 “Substituted amino” refers to the group - NRR 0.143 Arylaryl by itself or as part of another substituent, where each R is independently selected from the group con refers to a monovalent hydrocarbon group derived by the sisting of hydrogen, alkyl, Substituted alkyl, cycloalkyl, Sub removal of one hydrogen atom from a single carbon atom of stituted cycloalkyl, alkenyl, Substituted alkenyl, cycloalk a ring system in which two or more identical or non-identical enyl, Substituted cycloalkenyl, alkynyl. Substituted alkynyl, aromatic ring systems are joined directly together by a single aryl, heteroaryl, and heterocyclyl provided that at least one R bond, where the number of Such direct ring junctions is one is not hydrogen. less than the number of aromatic ring systems involved. Typi 0138 “Aminoacyl” refers to the group –C(O)NR'R'', cal arylaryl groups include, but are not limited to, biphenyl, wherein R and R’ independently are selected from the triphenyl, phenyl-napthyl, binaphthyl, biphenyl-napthyl, and group consisting of hydrogen, alkyl, Substituted alkyl, alk the like. When the number of carbon atoms in an arylaryl enyl, Substituted alkenyl, alkynyl. Substituted alkynyl, aryl, group is specified, the numbers refer to the carbon atoms Substituted aryl, cycloalkyl, Substituted cycloalkyl, cycloalk comprising each aromatic ring. For example, (C-C) ary enyl, substituted cycloalkenyl, heteroaryl, substituted het laryl is an arylaryl group in which each aromatic ring com eroaryl, heterocyclic, and substituted heterocyclic and where prises from 5 to 14 carbons, e.g., biphenyl, triphenyl, binaph R° and Rare optionally joined together with the nitrogen thyl, phenylnapthyl, etc. In certain embodiments, each bound thereto to form a heterocyclic or substituted heterocy aromatic ring system of an arylaryl group is independently a clic group, and wherein alkyl, Substituted alkyl, alkenyl, Sub (C-C) aromatic. In certain embodiments, each aromatic stituted alkenyl, alkynyl. Substituted alkynyl, cycloalkyl, Sub ring system of an arylaryl group is independently a (Cs-Co) stituted cycloalkyl, cycloalkenyl, Substituted cycloalkenyl, aromatic. In certain embodiments, each aromatic ring system aryl, substituted aryl, heteroaryl, substituted heteroaryl, het is identical, e.g., biphenyl, triphenyl, binaphthyl, trinaphthyl, erocyclic, and Substituted heterocyclic are as defined herein. etc. 0139 Alkoxy' by itself or as part of another substituent 0144). “Carboxyl,” “carboxy” or “carboxylate” refers to refers to a radical —OR where R represents an alkyl or —COH or salts thereof. cycloalkyl group as defined herein. Representative examples (0145 “Cyano” or “nitrile” refers to the group –CN. include, but are not limited to, methoxy, ethoxy, propoxy, 0146 “Cycloalkyl” by itselfor as part of another substitu butoxy, cyclohexyloxy and the like. ent refers to a Saturated or unsaturated cyclic alkyl radical. 0140 Alkoxycarbonyl by itself or as part of another Where a specific level of saturation is intended, the nomen substituent refers to a radical –C(O)CR' where R' repre clature “cycloalkanyl' or “cycloalkenyl is used. Typical sents an alkyl or cycloalkyl group as defined herein. Repre cycloalkyl groups include, but are not limited to, groups sentative examples include, but are not limited to, methoxy derived from cyclopropane, cyclobutane, cyclopentane, carbonyl, ethoxycarbonyl, propoxycarbonyl, cyclohexane and the like. In certain embodiments, the butoxycarbonyl, cyclohexyloxycarbonyl and the like. cycloalkyl group is (C-C) cycloalkyl. In certain embodi 0141 'Aryl by itself or as part of another substituent ments, the cycloalkyl group is (C-C) cycloalkyl. refers to a monovalent aromatic hydrocarbon radical derived 0147 “Cycloheteroalkyl or “heterocyclyl by itself or as by the removal of one hydrogen atom from a single carbon part of another Substituent, refers to a saturated or unsaturated atom of an aromatic ring system. Typical aryl groups include, cyclic alkyl radical in which one or more carbon atoms (and but are not limited to, groups derived from aceanthrylene, any associated hydrogen atoms) are independently replaced acenaphthylene, acephenanthrylene, anthracene, azulene, with the same or differentheteroatom. Typical heteroatoms to benzene, chrysene, coronene, fluoranthene, fluorene, replace the carbon atom(s) include, but are not limited to, N. hexacene, hexaphene, hexylene, as-indacene, S-indacene, P.O.S, Si, etc. Where a specific level of saturation is intended, indane, indene, naphthalene, octacene, octaphene, octalene, the nomenclature “cycloheteroalkanyl' or “cycloheteroalk ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, enyl is used. Typical cycloheteroalkyl groups include, but perylene, phenalene, phenanthrene, picene, pleiadene, are not limited to, groups derived from epoxides, azirines, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene thiranes, imidazolidine, morpholine, piperazine, piperidine, and the like. In certain embodiments, an aryl group comprises pyrazolidine, pyrrolidine, quinuclidine and the like. from 6 to 20 carbon atoms. In certain embodiments, an aryl 0148 “Heteroalkyl, Heteroalkanyl, Heteroalkenyl and group comprises from 6 to 12 carbon atoms. Examples of an Heteroalkynyl' by themselves or as part of another substitu aryl group are phenyl and naphthyl. ent refer to alkyl, alkanyl, alkenyl and alkynyl groups, respec 0142 "Arylalkyl by itselfor as part of another substituent tively, in which one or more of the carbon atoms (and any refers to an acyclic alkyl radical in which one of the hydrogen associated hydrogenatoms) are independently replaced with atoms bonded to a carbon atom, typically a terminal or sp the same or different heteroatomic groups. Typical heteroat carbonatom, is replaced with an aryl group. Typical arylalkyl omic groups which can be included in these groups include, groups include, but are not limited to, benzyl, 2-phenylethan but are not limited to. —O— —S——S—S— —O—S—, 1-yl 2-phenylethen-1-yl, naphthylmethyl 2-naphthylethan NR7R , —N N , N-N , N. N. 1-yl 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophe NR'R'', PR' , P(O), , POR - O P(O), nylethan-1-yl and the like. Where specific alkyl moieties are S-O-, -S (O) , -SO-, - SnR'R'' and the intended, the nomenclature arylalkanyl, arylalkenyl and/or like, where R7, R. R. R. R. R. R. and R are arylalkynyl is used. In certain embodiments, an arylalkyl independently hydrogen, alkyl, Substituted alkyl, aryl, Substi group is (C7-Co) arylalkyl, e.g., the alkanyl, alkenyl or alky tuted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substi nyl moiety of the arylalkyl group is (C-C) and the aryl tuted cycloalkyl, cycloheteroalkyl, substituted cyclohet US 2014/O121 152 A1 May 1, 2014 eroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, pentalene, pentaphene, perylene, phenalene, phenanthrene, substituted heteroaryl, heteroarylalkyl or substituted het picene, pleiadene, pyrene, pyranthrene, rubicene, triph eroarylalkyl. enylene, trinaphthalene and the like. 0149) “Heteroaryl' by itself or as part of another substitu 0153. “Heteroaromatic Ring System’ by itselfor as part of ent, refers to a monovalent heteroaromatic radical derived by another Substituent, refers to an aromatic ring system in the removal of one hydrogen atom from a single atom of a which one or more carbon atoms (and any associated hydro heteroaromatic ring system. Typical heteroaryl groups gen atoms) are independently replaced with the same or dif include, but are not limited to, groups derived from acridine, ferent heteroatom. Typical heteroatoms to replace the carbon arsindole, carbazole, B-carboline, chromane, chromene, cin atoms include, but are not limited to, N. P. O, S, Si, etc. noline, furan, imidazole, indazole, indole, indoline, indoliz Specifically included within the definition of "heteroaromatic ine, isobenzofuran, isochromene, isoindole, isoindoline, iso ring systems arefused ring systems in which one or more of quinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, the rings are aromatic and one or more of the rings are satu oxazole, perimidine, phenanthridine, phenanthroline, phena rated or unsaturated. Such as, for example, arsindole, benzo Zine, phthalazine, pteridine, purine, pyran, pyrazine, pyra dioxan, benzofuran, chromane, chromene, indole, indoline, Zole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, Xanthene, etc. Typical heteroaromatic ring systems include, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, but are not limited to, arsindole, carbazole, B-carboline, chro thiadiazole, thiazole, thiophene, triazole, Xanthene, benzo mane, chromene, cinnoline, furan, imidazole, indazole, dioxole and the like. In certain embodiments, the heteroaryl indole, indoline, indolizine, isobenzofuran, isochromene, group is from 5-20 membered heteroaryl. In certain embodi isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, ments, the heteroaryl group is from 5-10 membered het naphthyridine, oxadiazole, oxazole, perimidine, phenanthri eroaryl. In certain embodiments, heteroaryl groups are those dine, phenanthroline, phenazine, phthalazine, pteridine, derived from thiophene, pyrrole, benzothiophene, benzofu purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyri ran, indole, pyridine, quinoline, imidazole, oxazole and pyra midine, pyrrole, pyrrolizine, quinazoline, quinoline, quino Z10. lizine, quinoxaline, tetrazole, thiadiazole, thiazole, 0150 “Heteroarylalkyl by itself or as part of another thiophene, triazole, Xanthene and the like. substituent, refers to an acyclic alkyl radical in which one of 0154 “Substituted” refers to a group in which one or more the hydrogen atoms bonded to a carbon atom, typically a hydrogenatoms are independently replaced with the same or terminal or sp carbon atom, is replaced with a heteroaryl different substituent(s). Typical substituents include, but are group. Where specific alkyl moieties are intended, the not limited to, alkylenedioxy (such as methylenedioxy), -M, nomenclature heteroarylalkanyl, heteroarylalkenyl and/or R, O, —O, OR, SR, S, S, NR'R'', heteroarylalkynyl is used. In certain embodiments, the het =NR, CF, CN, OCN, SCN, NO, NO, eroarylalkyl group is a 6-30 membered heteroarylalkyl, e.g., =N-N-S(O).O. —S(O),OH, -S(O).R', OS(O) the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl O, OS(O).R°, -P(O)(O), -P(O)(OR)(O), OP is 1-10 membered and the heteroaryl moiety is a 5-20-mem (O)(OR)(OR), C(O)R, C(S)R, C(O)OR, bered heteroaryl. In certain embodiments, the heteroarylalkyl C(O)NR'R'', C(O)O, C(S)OR, NRC(O) group is 6-20 membered heteroarylalkyl, e.g., the alkanyl. NR60R6, NR2C(S)NR'Rol, NR62C(NR63)NR'Rol alkenyl or alkynyl moiety of the heteroarylalkyl is 1-8 mem and C(NR)NR'R'' where M is halogen; R. R. R. bered and the heteroaryl moiety is a 5-12-membered het and Rare independently hydrogen, alkyl, substituted alkyl, eroaryl. alkoxy, Substitutedalkoxy, cycloalkyl, Substituted cycloalkyl, 0151. “Heterocycle,” “heterocyclic,” “heterocycloalkyl.” cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substi and "heterocyclyl refer to a saturated or unsaturated group tuted aryl, heteroaryl or substituted heteroaryl, or optionally having a single ring or multiple condensed rings, including R" and R' together with the nitrogenatom to which they are fused bridged and spiro ring systems, and having from 3 to 15 bonded form a cycloheteroalkyl or substituted cyclohet ring atoms, including 1 to 4 hetero atoms. These hetero atoms eroalkyl ring; and Rand Rare independently hydrogen, are selected from the group consisting of nitrogen, Sulfur, or alkyl, substituted alkyl, aryl, cycloalkyl, substituted oxygen, wherein, in fused ring systems, one or more of the cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, rings can be cycloalkyl, aryl, or heteroaryl, provided that the aryl, substituted aryl, heteroaryl or substituted heteroaryl, or point of attachment is through the non-aromatic ring. In cer optionally R'' and R together with the nitrogen atom to tain embodiments, the nitrogen and/or Sulfur atom(s) of the which they are bonded form a cycloheteroalkyl or substituted heterocyclic group are optionally oxidized to provide for the cycloheteroalkyl ring. In certain embodiments, Substituents N-oxide. —S(O)—, or —SO - moieties. include -M, R', -O, OR', SR, S, -S, 0152 “Aromatic Ring System” by itself or as part of NR'R'', = NR, CF, CN, OCN, SCN, NO, another Substituent, refers to an unsaturated cyclic or polycy - NO. —N, - N - S(O).R', —OS(O).O, OS(O) clic ring system having a conjugated at electron system. Spe R, P(O)(O), P(O)(OR)(O), OP(O)(OR) cifically included within the definition of “aromatic ring sys (OR), C(O)R, C(S)R, C(O)OR, C(O) tem” are fused ring systems in which one or more of the rings NR'R'', C(O)O, NRC(O)NR'R''. In certain are aromatic and one or more of the rings are saturated or embodiments, substituents include -M, R', unsaturated, such as, for example, fluorene, indane, indene, —O, OR, SR, NR'R'', CF, CN, NO, phenalene, etc. Typical aromatic ring systems include, but are S(O),R, P(O)(OR)(O), OP(O)(OR)(OR), not limited to, aceanthrylene, acenaphthylene, acephenan C(O)R, C(O)OR, C(O)NR'R'', C(O)O. In thrylene, anthracene, azulene, benzene, chrysene, coronene, certain embodiments, substituents include -M, R', fluoranthene, fluorene, hexacene, hexaphene, hexylene, as —O, OR, SR, NR'R'', CF, CN, NO, indacene, S-indacene, indane, indene, naphthalene, octacene, S(O),R, OP(O)(OR)(OR), C(O)R, C(O) octaphene, octalene, ovalene, penta-2,4-diene, pentacene, OR, C(O)O, where R, R and R are as defined US 2014/O121 152 A1 May 1, 2014 above. For example, a Substituted group may bear a methyl 0.165 “Pharmaceutically acceptable salt” refers to a salt of enedioxy Substituent or one, two, or three Substituents a compound, which possesses the desired pharmacological selected from a halogen atom, a (1-4C)alkyl group and a activity of the compound. Such salts include: (1) acid addition (1-4C)alkoxy group. salts, formed with inorganic acids such as hydrochloric acid, 0155. It is understood that in all substituted groups defined hydrobromic acid, Sulfuric acid, nitric acid, phosphoric acid, above, polymers arrived at by defining substituents with fur and the like; or formed with organic acids such as acetic acid, ther substituents to themselves (e.g., Substituted aryl having a propionic acid, hexanoic acid, cyclopentanepropionic acid, substituted aryl group as a substituent which is itself substi glycolic acid, pyruvic acid, lactic acid, malonic acid, Succinic tuted with a substituted aryl group, which is further substi acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric tuted by a Substituted aryl group, etc.) are not intended for acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cin inclusion herein. In Such cases, the maximum number of such namic acid, mandelic acid, methanesulfonic acid, ethane substitutions is three. For example, serial substitutions of Sulfonic acid, 1.2-ethane-disulfonic acid, 2-hydroxyethane substituted aryl groups are limited to substituted aryl-(substi sulfonic acid, benzenesulfonic acid, tuted aryl)-substituted aryl. 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 0156. As to any of the groups disclosed herein which 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicy contain one or more Substituents, it is understood, of course, clo2.2.2-oct-2-ene-1-carboxylic acid, glucoheptonic acid, that such groups do not contain any Substitution or Substitu 3-phenylpropionic acid, trimethylacetic acid, tertiary buty tion patterns which are sterically impractical and/or syntheti lacetic acid, lauryl Sulfuric acid, gluconic acid, glutamic acid, cally non-feasible. In addition, the Subject compounds hydroxynaphthoic acid, Salicylic acid, Stearic acid, muconic include all stereochemical isomers arising from the Substitu acid, and the like; or (2) salts formed when an acidic proton tion of these compounds. present in the compound is replaced by a metal ion, e.g., an O157. Unless indicated otherwise, the nomenclature of alkali metalion, an alkaline earth ion, oran aluminum ion; or substituents that are not explicitly defined herein are arrived coordinates with an organic base Such as ethanolamine, at by naming the terminal portion of the functionality fol diethanolamine, triethanolamine, N-methylglucamine and lowed by the adjacent functionality toward the point of the like. attachment. For example, the substituent “arylalkyloxycarbo (0166 “Pharmacodynamic (PD) profile” refers to a profile nyl refers to the group (aryl)-(alkyl)-O C(O)—. of the efficacy of a drug in a patient (or Subject or user), which 0158 “Dose unit as used herein refers to a combination is characterized by PD parameters. “PD parameters' include of a GI enzyme-cleavable prodrug (e.g., trypsin-cleavable 'drug Emax” (the maximum drug efficacy), "drug EC50 (the prodrug) and a GI enzyme inhibitor (e.g., a trypsin inhibitor). concentration of drug at 50% of the Emax) and side effects. A 'single dose unit is a single unit of a combination of a GI 0.167 “PK parameter refers to a measure of drug concen enzyme-cleavable prodrug (e.g., trypsin-cleavable prodrug) tration in blood or plasma, Such as: 1) "drug Cmax', the and a GI enzyme inhibitor (e.g., trypsin inhibitor), where the maximum concentration of drug achieved in blood or plasma; single dose unit provide atherapeutically effective amount of 2) "drug Tmax', the time elapsed following ingestion to drug (i.e., a Sufficient amount of drug to effect a therapeutic achieve Cmax; and 3) "drug exposure', the total concentra effect, e.g., a dose within the respective drugs therapeutic tion of drug present in blood or plasma over a selected period window, or therapeutic range). “Multiple dose units” or “mul of time, which can be measured using the area under the curve tiples of a dose unit' or a “multiple of a dose unit refers to at (AUC) of a time course of drug release over a selected period least two single dose units. of time (t). Modification of one or more PK parameters pro 0159) “Gastrointestinal enzyme” or “GI enzyme” refers to vides for a modified PK profile. an enzyme located in the gastrointestinal (GI) tract, which encompasses the anatomical sites from mouth to anus. 0168 “PK profile' refers to a profile of drug concentration Trypsin is an example of a GI enzyme. in blood or plasma. Sucha profile can be a relationship of drug 0160 “Gastrointestinal enzyme-cleavable moiety' or “GI concentration over time (i.e., a “concentration-time PK pro enzyme-cleavable moiety refers to a group comprising a site file') or a relationship of drug concentration versus number of Susceptible to cleavage by a GI enzyme. For example, a doses ingested (i.e., a “concentration-dose PK profile'). APK "trypsin-cleavable moiety refers to a group comprising a site profile is characterized by PK parameters. Susceptible to cleavage by trypsin. (0169. “Preventing or “prevention” or “prophylaxis' 0161 "Gastrointestinal enzyme inhibitor” or “GI enzyme refers to a reduction in risk of occurrence of a condition, Such inhibitor refers to any agent capable of inhibiting the action as pain. of a gastrointestinal enzyme on a Substrate. The term also 0170 “Prodrug” refers to a derivative of an active agent encompasses salts of gastrointestinal enzyme inhibitors. For that requires a transformation within the body to release the example, a "trypsin inhibitor refers to any agent capable of active agent. In certain embodiments, the transformation is an inhibiting the action of trypsin on a substrate. enzymatic transformation. In certain embodiments, the trans 0162 “Patient includes humans, and also other mam formation is a cyclization transformation. In certain embodi mals, such as livestock, Zoo animals, and companion animals, ments, the transformation is a combination of an enzymatic Such as a cat, dog, or horse. transformation and a cyclization transformation. Prodrugs 0163 “Pharmaceutical composition” refers to at least one are frequently, although not necessarily, pharmacologically compound and can further comprise a pharmaceutically inactive until converted to the active agent. acceptable carrier, with which the compound is administered 0171 "Promoiety” refers to a form of protecting group to a patient. that when used to mask a functional group within an active 0164 "Pharmaceutically acceptable carrier' refers to a agent converts the active agent into a prodrug. Typically, the diluent, adjuvant, excipient or vehicle with, or in which a promoiety will be attached to the drug via bond(s) that are compound is administered. cleaved by enzymatic or non-enzymatic means in vivo. US 2014/O121 152 A1 May 1, 2014

0172 "Solvate” as used herein refers to a complex or methods and materials are now described. All publications aggregate formed by one or more molecules of a solute, e.g. a mentioned herein are incorporated herein by reference to prodrug or a pharmaceutically acceptable salt thereof, and disclose and describe the methods and/or materials in con one or more molecules of a solvent. Such Solvates are typi nection with which the publications are cited. cally crystalline solids having a Substantially fixed molar ratio 0180 Except as otherwise noted, the methods and tech of solute and solvent. Representative solvents include by way niques of the present embodiments are generally performed of example, water, methanol, ethanol, isopropanol, acetic according to conventional methods well known in the art and acid, and the like. When the solvent is water, the solvate as described in various general and more specific references formed is a hydrate. that are cited and discussed throughout the present specifica 0173 “Therapeutically effective amount’ means the tion. See, e.g., Loudon, Organic Chemistry, Fourth Edition, amount of a compound (e.g., prodrug) that, when adminis New York: Oxford University Press, 2002, pp. 360-361, tered to a patient for preventing or treating a condition Such as 1084-1085; Smith and March, March's Advanced Organic pain, is sufficient to effect such treatment. The “therapeuti Chemistry: Reactions, Mechanisms, and Structure, Fifth Edi cally effective amount” will vary depending on the com tion, Wiley-Interscience, 2001. pound, the condition and its severity and the age, weight, etc., 0181. The nomenclature used herein to name the subject of the patient. compounds is illustrated in the Examples herein. In certain 0.174 “Treating or “treatment of any condition, such as instances, this nomenclature has is derived using the commer pain, refers, in certain embodiments, to ameliorating the con cially-available AutoNom software (MDL, San Leandro, dition (i.e., arresting or reducing the development of the con Calif.). dition). In certain embodiments “treating or “treatment' 0182. It is appreciated that certain features of the inven refers to ameliorating at least one physical parameter, which tion, which are, for clarity, described in the context of separate may not be discernible by the patient. In certain embodi embodiments, may also be provided in combination in a ments, “treating or “treatment” refers to inhibiting the con single embodiment. Conversely, various features of the dition, either physically, (e.g., stabilization of a discernible invention, which are, for brevity, described in the context of a symptom), physiologically, (e.g., stabilization of a physical single embodiment, may also be provided separately or in any parameter), or both. In certain embodiments, “treating” or suitable sub-combination. All combinations of the embodi “treatment” refers to delaying the onset of the condition. ments pertaining to the chemical groups represented by the variables are specifically embraced by the present invention DETAILED DESCRIPTION and are disclosed hereinjust as if each and every combination (0175 Before the present invention is further described, it was individually and explicitly disclosed, to the extent that is to be understood that this invention is not limited to par Such combinations embrace compounds that are stable com ticular embodiments described, as such may, of course, vary. pounds (i.e., compounds that can be isolated, characterised, It is also to be understood that the terminology used herein is and tested for biological activity). In addition, all Sub-com for the purpose of describing particular embodiments only, binations of the chemical groups listed in the embodiments and is not intended to be limiting, since the scope of the describing Such variables are also specifically embraced by present invention will be limited only by the appended claims. the present invention and are disclosed herein just as if each 0176 It must be noted that as used herein and in the and every Such sub-combination of chemical groups was appended claims, the singular forms “a,” “an and “the individually and explicitly disclosed herein. include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to General Synthetic Procedures exclude any optional element. As such, this statement is 0183. Many general references providing commonly intended to serve as antecedent basis for use of such exclusive known chemical synthetic schemes and conditions useful for terminology as “solely.” “only' and the like in connection synthesizing the disclosed compounds are available (see, e.g., with the recitation of claim elements, or use of a “negative' Smith and March, March's Advanced Organic Chemistry: limitation. Reactions, Mechanisms, and Structure, Fifth Edition, Wiley 0177. It should be understood that as used herein, the term Interscience, 2001; or Vogel, A Textbook of Practical Organic “a” entity or “an entity refers to one or more of that entity. Chemistry, Including Qualitative Organic Analysis, Fourth For example, a compound refers to one or more compounds. Edition, New York: Longman, 1978). As such, the terms “a”, “an”, “one or more' and “at least one' 0.184 Compounds as described herein can be purified by can be used interchangeably. Similarly the terms "compris any of the means known in the art, including chromatographic ing”, “including and “having can be used interchangeably. means, such as high performance liquid chromatography 0.178 The publications discussed herein are provided (HPLC), preparative thin layer chromatography, flash col solely for their disclosure prior to the filing date of the present umn chromatography and ion exchange chromatography. application. Nothing herein is to be construed as an admission Any Suitable stationary phase can be used, including normal that the present invention is not entitled to antedate such and reversed phases as well as ionic resins. See, e.g., Intro publication by virtue of prior invention. Further, the dates of duction to Modern Liquid Chromatography, 2nd Edition, ed. publication provided may be different from the actual publi L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; cation dates which may need to be independently confirmed. and Thin Layer Chromatography, ed. E. Stahl, Springer-Ver 0179 Unless defined otherwise, all technical and scien lag, New York, 1969. tific terms used herein have the same meaning as commonly 0185. During any of the processes for preparation of the understood by one of ordinary skill in the art to which this compounds of the present disclosure, it may be necessary invention belongs. Although any methods and materials simi and/or desirable to protect sensitive or reactive groups on any lar or equivalent to those described herein can also be used in of the molecules concerned. This can beachieved by means of the practice or testing of the present invention, the preferred conventional protecting groups as described in standard US 2014/O121 152 A1 May 1, 2014

works, such as T. W. Greene and P. G. M. Wuts, “Protective 0191 The enzyme capable of cleaving the enzyme-cleav Groups in Organic Synthesis'. Fourth edition, Wiley, New able moiety can be a peptidase, also referred to as a pro York 2006. The protecting groups can be removed at a con tease—the enzyme-cleavable moiety being linked to the Venient Subsequent stage using methods known from the art. nucleophilic nitrogen through an amide (e.g. a peptide: 0186 The compounds described herein can contain one or —NHCO—) bond. In some embodiments, the enzyme is a more chiral centers and/or double bonds and therefore, can digestive enzyme. Such as a digestive enzyme of a protein. exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Accord 0.192 The enzyme-cleavable moiety linked to the nucleo ingly, all possible enantiomers and stereoisomers of the com philic nitrogen through an amide bond can be, for example, a pounds including the stereoisomerically pure form (e.g., geo residue of an amino acid or a peptide, a variant of a residue of metrically pure, enantiomerically pure or diastereomerically an amino acid or a peptide, a derivative of a residue of an pure) and enantiomeric and stereoisomeric mixtures are amino acid or a peptide, or a derivative of a residue of an included in the description of the compounds herein. Enan amino acid variant or a peptide variant. As discussed below, tiomeric and stereoisomeric mixtures can be resolved into anamino acid variant refers to an amino acid other than any of their component enantiomers or stereoisomers using separa the 20 common naturally occurring L-amino acids that is tion techniques or chiral synthesis techniques well known to hydrolyzable by a protease in a manner similar to the ability the skilled artisan. The compounds can also exist in several of a protease to hydrolyze a naturally occurring L-amino acid. tautomeric forms including the enol form, the keto form and A derivative refers to a substance that has been altered from mixtures thereof. Accordingly, the chemical structures another Substance by modification, partial Substitution, depicted herein encompass all possible tautomeric forms of homologation, truncation, or a change in oxidation state. For the illustrated compounds. example, an N-acyl derivative of an amino acid is an example 0187. The compounds described also include isotopically of a derivative of an amino acid. labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in 0193 In some instances, the enzyme-cleavable moiety can nature. Examples of isotopes that can be incorporated into the bean (alpha) N-acyl derivative of an amino acid or peptide or compounds disclosed herein include, but are not limited to, an (alpha) N-acyl derivative of an amino acid variant or pep *H, H, C, C, C, 'N, O, 7O, etc. Compounds can tide variant. exist in unsolvated forms as well as Solvated forms, including 0194 The peptide can contain, for example, up to about hydrated forms. In general, compounds can be hydrated or 100 amino acid residues. Each amino acid can advanta Solvated. Certain compounds can exist in multiple crystalline geously be a naturally occurring amino acid, such as an or amorphous forms. In general, all physical forms are L-amino acid. Examples of naturally occurring amino acids equivalent for the uses contemplated herein and are intended are alanine, arginine, asparagine, aspartic acid, cysteine, to be within the scope of the present disclosure. glutamic acid, glutamine, glycine, histidine, isoleucine, leu cine, lysine, methionine, phenylalanine, proline, serine, Representative Embodiments threonine, tryptophan, tyrosine and Valine. Accordingly, 0188 Reference will now be made in detail to various examples of enzyme-cleavable moieties include residues of embodiments. It will be understood that the invention is not the L-amino acids listed herein and N-acyl derivatives limited to these embodiments. To the contrary, it is intended to thereof, and peptides formed from at least two of the L-amino cover alternatives, modifications, and equivalents as may be acids listed herein and the N-acyl derivatives thereof. Addi included within the spirit and scope of the allowed claims. tional examples include residues of amino acid variants and 0189 The disclosure provides a method of providing a N-acyl derivatives thereof, and peptides formed from at least patient with post administration-activated, controlled release two of the L-amino acids listed above and/or variants thereof, of an active agent, which comprises administering to the and N-acyl derivatives thereof. Also included are derivatives patient a corresponding compound in which the active agent of Such amino acids or amino acid variants and peptides has a Substituent which is a spacer leaving group bearing a thereof. nucleophilic nitrogen that is protected with an enzyme-cleav able moiety, the configuration of the spacer leaving group 0.195 The embodiments provide a prodrug with a substitu being Such that, upon enzymatic cleavage of the cleavable ent which is a spacer leaving group bearing a nucleophilic moiety, the nucleophilic nitrogen is capable of forming a nitrogen that is protected with an enzyme-cleavable moiety. cyclic urea, liberating the compound from the spacer leaving Upon enzymatic cleavage of the cleavable moiety, the nucleo group so as to provide the patient with controlled release of an philic nitrogen is capable of forming a cyclic urea. A repre active agent. sentative scheme of a cyclization of a spacer group is shown 0190. The corresponding compound (prodrug in accor below, wherein X is an active agent. dance with the present disclosure) provides post administra tion-activated, controlled release of an active agent, because it requires enzymatic cleavage to initiate release of the com pound, and because the rate of release of the active agent depends upon both the rate of enzymatic cleavage and the rate of cyclization. The prodrug is configured so that it will not provide excessively high plasma levels of the active agentif it is administered inappropriately, and cannot readily be decomposed to afford the active agent other than by enzy (Y), matic cleavage followed by controlled cyclization. US 2014/O121 152 A1 May 1, 2014 12

-continued hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to —C(O) NI (A ring)-Y— (CRR). NH CO) CH(R) N(R) C(O) CH (R) N(R) R': a residue of a phenolic active agent, wherein the hydrogenatom of the phenolic hydroxyl group is A + X replaced by a covalent bond to —C(O) N(A ring)-Y- x-k (CRR). NH CO) CH(R) N(R) C(O) CH (Y), (R) N(R) R', and a residue of an amide-containing active agent, wherein —C(O) N(A ring)-Y—(CRR) The rate of cyclization of the cyclic urea can be adjusted by NH C(O) CH(R) N(R) C(O) CH(R) N incorporation of a heterocyclic ring within the spacer group. (R) R' is connected to the amide-containing active agent In certain embodiments, incorporation of a heterocyclic ring through the oxygen of the amide group, wherein the amide within the spacer group results in formation of a fused ring group is converted to an amide enol or an imine tautomer, cyclic urea and in a faster cyclization reaction. 0204 the A ring is a heterocyclic 5 to 12-membered ring: 0196. The cyclic group formed when the active agent is 0205 each Y is independently selected from alkyl, substi released is conveniently pharmaceutically acceptable, in par tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted ticular a pharmaceutically acceptable cyclic urea. It will be alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car appreciated that cyclic ureas are generally very stable and boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa have low toxicity. cyl. Substituted aminoacyl, amino, Substituted amino, acy 0.197 According to one aspect, the embodiments include lamino, Substituted acylamino, and cyano; pharmaceutical compositions, which comprise a GI enzyme 0206 c is a number from Zero to 3: cleavable active agent prodrug and an optional GI enzyme 0207 each R" is independently selected from hydrogen, inhibitor. Examples of active agent prodrugs and enzyme alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, inhibitors are described below. substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, Active Agent Prodrugs aminoacyl, Substituted aminoacyl, amino, Substituted amino, acylamino, Substituted acylamino, and cyano; 0198 An "active agent” refers to a chemical substance that 0208 each R is independently selected from hydrogen, exerts a pharmacological action. Examples of active agents alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, include, but are not limited to, active agents that are suscep substituted alkynyl, aryl, substituted aryl, acyl, substituted tible to misuse, abuse, or overdose. Certain examples of active acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, agents include, but are not limited to, opioids, NSAIDs, other aminoacyl, Substituted aminoacyl, amino, Substituted amino, analgesics, GABA agonists, GABA antagonists, and psycho acylamino, Substituted acylamino, and cyano; or stimulants. 0209 RandR together with the carbon to which they are 0199 The disclosure provides a prodrug which provides attached can form a cycloalkyl or Substituted cycloalkyl enzymatically-controlled release of an active agent. The dis group, or two R' or R groups on adjacent carbon atoms, closure provides a promoiety that is attached to an active together with the carbonatoms to which they are attached, can agent through any Suitable structural moiety on the drug, form a cycloalkyl or Substituted cycloalkyl group; where the structural moiety has a reactive group. Examples of 0210 a is an integer from one to 8: reactive groups on an active agent include, but are not limited 0211 provided that when a is one, the A ring is a hetero to, ketone, phenol, and amide. cyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to Formula I 8: 0200 Compounds of the present disclosure include com 0212 each R is independently hydrogen, alkyl, substi pounds of formula I shown below. Compositions of the tuted alkyl, aryl or substituted aryl; present disclosure also include compounds of formula I 0213 R is selected from hydrogen, alkyl, substituted shown below. Pharmaceutical compositions and methods of alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, the present disclosure also contemplate compounds of for heteroalkyl, substituted heteroalkyl, heteroaryl, substituted mula I. heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl: 0201 The present embodiments provide a compound of 10214) each R is independently selected from hydrogen, formula I: alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, sub stituted arylalkyl, heteroalkyl, substituted heteroalkyl, het eroaryl, substituted heteroaryl, heteroarylalkyl, and substi (I) tuted heteroarylalkyl: O R R2 O R3 R6 0215 b is a number from Zero to 100; and -l N R7 0216) R' is selected from hydrogen, alkyl, substituted N a NN N alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted A alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi H R5 O R tuted arylalkyl: (Y), 0217 or a salt, hydrate or solvate thereof. Opioid Prodrugs 0202 wherein 0203 X is selected from a residue of a ketone-containing 0218. An "opioid refers to a chemical substance that active agent, wherein the hydrogenatom of the corresponding exerts its pharmacological action by interaction at an opioid US 2014/O121 152 A1 May 1, 2014 receptor. An opioid can be a natural product, a synthetic 0228 each R" is independently selected from hydrogen, compound or a semi-synthetic compound. In certain embodi alkyl, substituted alkyl, alkenyl, substituted alkenyl, ments, an opioid is a compound with a pharmacophore that alkynyl. Substituted alkynyl, aryl, Substituted aryl, acyl, presents to the opioid receptor an aromatic group and an Substituted acyl, carboxyl, alkoxycarbonyl, Substituted aliphatic amine group in an architecturally discrete way. See, alkoxycarbonyl, aminoacyl, Substituted aminoacyl, for example, Foye's Principles of Medicinal Chemistry, Sixth amino, Substituted amino, acylamino, Substituted acy Edition, ed. T. L. Lemke and D. A. Williams, Lippincott lamino, and cyano; Williams & Wilkins, 2008, particularly Chapter 24, pages 10229 each R is independently selected from hydrogen, 653-678. alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, 0219. The disclosure provides an opioid prodrug that pro substituted alkynyl, aryl, substituted aryl, acyl, substituted vides controlled release of an opioid. The disclosure provides acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, a promoiety that is attached to an opioid through any struc aminoacyl, Substituted aminoacyl, amino, Substituted amino, tural moiety on the opioid, where the structural moiety has a acylamino, Substituted acylamino, and cyano; or reactive group. Examples of reactive groups on an opioid 0230) R' and R together with the carbon to which they are include, but are not limited to ketone, phenol, and amide. attached can form a cycloalkyl or Substituted cycloalkyl 0220. It is contemplated that opioids bearing at least some group, or two R' or R groups on adjacent carbon atoms, of the functionalities described herein will be developed; such together with the carbonatoms to which they are attached, can opioids are included as part of the scope of this disclosure. form a cycloalkyl or Substituted cycloalkyl group; 0231 a is an integer from one to 8: Formula II 0232 provided that when a is one, the A ring is a hetero cyclic 6 to 12-membered ring; and when the A ring is a 0221 Compounds of the present disclosure include com heterocyclic 5-membered ring, then a is an integer from 2 to pounds of formula II shown below. Compositions of the 8: present disclosure also include compounds of formula II 0233 each R is independently hydrogen, alkyl, substi shown below. Pharmaceutical compositions and methods of tuted alkyl, aryl or substituted aryl; the present disclosure also contemplate compounds of for 0234 R is selected from hydrogen, alkyl, substituted mula II. alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, 0222. The present embodiments provide a compound of heteroalkyl, substituted heteroalkyl, heteroaryl, substituted formula II: heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; 0235 each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, sub stituted arylalkyl, heteroalkyl, substituted heteroalkyl, het eroaryl, substituted heteroaryl, heteroarylalkyl, and substi tuted heteroarylalkyl: 0236 b is a number from Zero to 100; and 0237 R’ is selected from hydrogen, alkyl, substituted alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted (Y), alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi tuted arylalkyl: 0223 wherein 0238 or a salt, hydrate or solvate thereof. 0239 Informula II, X can be selected from a residue of a 0224 X is selected from a residue of a ketone-containing ketone-containing opioid, wherein the hydrogen atom of the opioid, wherein the hydrogen atom of the corresponding corresponding hydroxyl group of the enolic tautomer of the hydroxyl group of the enolic tautomer of the ketone is ketone is replaced by a covalent bond to —C(O) N(A replaced by a covalent bond to —C(O)—N(A ring)-Y— ring)-Y-(CRR). NH C(O)-CH(R) N(R)-C (CRR). NH C(O)-CH(R) N(R)-C(O)-CH (O) CH(R) N(R) R'; a residue of a phenolic opioid, (R) N(R) R', a residue of a phenolic opioid, wherein wherein the hydrogenatom of the phenolic hydroxyl group is the hydrogenatom of the phenolic hydroxyl group is replaced replaced by a covalent bond to —C(O) N(A ring)-Y- by a covalent bond to —C(O) N(A ring)-Y (CRR) (CRR). NH CO) CH(R) N(R) C(O) CH NH C(O) CH(R) N(R) C(O) CH(R) N (R) N(R) R', and a residue of an amide-containing (R) R', and a residue of an amide-containing opioid, opioid, wherein - C(O) N(A ring)-Y-(CRR) wherein –C(O) N(A ring)-Y-(CRR). NH C NH CO) CH(R) N(R) C(O) CH(R) N(R) (O) CH(R) N(R)-C(O)-CH(R) N(R) R7 is R is connected to the amide-containing opioid through connected to the amide-containing opioid through the oxygen the oxygen of the amide group, wherein the amide group is of the amide group, wherein the amide group is converted to converted to an amide enol or an imine tautomer. an amide enol or an imine tautomer, 0240. In certain instances, X is a ketone-containing 0225 the A ring is a heterocyclic 5 to 12-membered ring; opioid, wherein the hydrogen atom of the corresponding 0226 each Y is independently selected from alkyl, substi hydroxyl group of the enolic tautomer of the ketone is tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted replaced by a covalent bond to —C(O) NI (A ring)-Y— alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car (CRR). NH C(O)-CH(R) N(R)-C(O)-CH boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa (R) N(R) R7. cyl. Substituted aminoacyl, amino, Substituted amino, acy 0241. In certain instances, X is a ketone-containing lamino, Substituted acylamino, and cyano; opioid, wherein the opioid is selected from acetylmorphone, 0227 c is a number from Zero to 3: hydrocodone, hydromorphone, ketobemidone, methadone, US 2014/O121 152 A1 May 1, 2014 naloxone, naltrexone, N-methylnaloxone, N-methylmaltrex 0249. The present embodiments provide a compound of one, oxycodone, oxymorphone, and pentamorphone. formula IIIa: 0242. In certain instances, X is a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—N (A ring)- (IIIa) Y. (CRR). NH CO) CH(R) N(R) C(O) O R R2 O R3 R6 CH(R) N(R) R7. -l N R 7 0243 In certain instances, X is a phenolic opioid, wherein X N a NN --- N A 5 the opioid is selected from buprenorphine, dihydroetorphine, H R O R3 diprenorphine, etorphine, hydromorphone, levorphanol, (Y), morphine, nalbuphine, nalmefene, nalorphine, naloxone, nal trexone, N-methyldiprenorphine, N-methylnaloxone, N-me thylmaltrexone, oripavine, oxymorphone, butorphanol, dezo 0250 wherein cine, ketobemidone, meptazinol, o-desmethyltramadol, 0251 X represents a residue of a ketone-containing active pentazocine, phenazocine, and tapentadol. agent, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is 0244. In certain instances, X is a residue of an amide replaced by a covalent bond to —C(O) N(A ring)-Y- containing opioid, wherein —C(O)—NI (A ring)-Y— (CRR). NH CO) CH(R) N(R) C(O) CH (CRR). NH CO) CH(R) N(R) C(O) CH (R) N(R) R7: (R) N(R) R' is connected to the amide-containing 0252 the A ring is a heterocyclic 5 to 12-membered ring: opioid through the oxygen of the amide group, wherein the 0253) each Y is independently selected from alkyl, substi amide group is converted to an amide enol or an imine tau tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted tOmer. alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car 0245. In certain instances, X is an amide-containing boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa opioid, wherein the opioid is selected from alfentanil, carfen cyl. Substituted aminoacyl, amino, Substituted amino, acy tanil, fentanyl, lofentanil, loperamide, olmefentanyl. lamino, Substituted acylamino, and cyano; remifentanil, and Sufentanil. 0254) c is a number from Zero to 3: (0255 each R" is independently selected from hydrogen, alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, Ketone-Modified Active Agent Prodrugs substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, 0246 The disclosure provides a ketone-modified active agent prodrug that provides controlled release of a ketone aminoacyl, Substituted aminoacyl, amino, Substituted amino, containing active agent. In a ketone-modified active agent acylamino, Substituted acylamino, and cyano; prodrug, a promoiety is attached to the ketone-containing 0256 each R is independently selected from hydrogen, active agent through the enolic oxygen atom of the ketone alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, moiety. In a ketone-modified active agent prodrug, the hydro substituted alkynyl, aryl, substituted aryl, acyl, substituted gen atom of the corresponding hydroxyl group of the enolic acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, tautomer of the ketone-containing active agent is replaced by aminoacyl, Substituted aminoacyl, amino, Substituted amino, a covalent bond to a promoiety. acylamino, Substituted acylamino, and cyano; or 0257 RandR together with the carbon to which they are 0247. As disclosed herein, an enzyme-cleavable ketone attached can form a cycloalkyl or Substituted cycloalkyl modified active agent prodrug is a ketone-modified active group, or two R' or R groups on adjacent carbon atoms, agent prodrug that comprises a promoiety comprising an together with the carbonatoms to which they are attached, can enzyme-cleavable moiety, i.e., a moiety having a site Suscep form a cycloalkyl or Substituted cycloalkyl group; tible to cleavage by an enzyme. In one embodiment, the cleavable moiety is a GI enzyme-cleavable moiety, Such as a 0258 a is an integer from one to 8: trypsin-cleavable moiety. Such a prodrug comprises a ketone 0259 provided that when a is one, the A ring is a hetero containing active agent covalently bound to a promoiety com cyclic 6 to 12-membered ring; and when the A ring is a prising an enzyme-cleavable moiety, wherein cleavage of the heterocyclic 5-membered ring, then a is an integer from 2 to enzyme-cleavable moiety by an enzyme mediates release of 8: the drug. 0260 each R is independently hydrogen, alkyl, substi tuted alkyl, aryl or substituted aryl; 10261) R' is selected from hydrogen, alkyl, substituted Formulae III-VI alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, 0248 Compounds of the present disclosure include com heteroalkyl, substituted heteroalkyl, heteroaryl, substituted pounds of formulae III-VI shown below. Compositions of the heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl: present disclosure also include compounds of formulae III-VI 10262 each R is independently selected from hydrogen, shown below. Pharmaceutical compositions and methods of alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, sub the present disclosure also contemplate compounds of formu stituted arylalkyl, heteroalkyl, substituted heteroalkyl, het lae III-VI. Reference to the formula number is meant to eroaryl, substituted heteroaryl, heteroarylalkyl, and substi include compounds of both the “a” and “b' versions of the tuted heteroarylalkyl: formula number. 0263 b is a number from Zero to 100; and US 2014/O121 152 A1 May 1, 2014

0264) R' is selected from hydrogen, alkyl, substituted group, or two R' or R groups on adjacent carbon atoms, alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted together with the carbonatoms to which they are attached, can alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi form a cycloalkyl or Substituted cycloalkyl group; tuted arylalkyl: 0275 a is an integer from one to 8: 0265 or a salt, hydrate or solvate thereof. 0276 provided that when a is one, the A ring is a hetero 0266 The present embodiments provide a compound of cyclic 6 to 12-membered ring; and when the A ring is a formula IIIb: heterocyclic 5-membered ring, then a is an integer from 2 to 8: (0277 each R is independently hydrogen, alkyl, substi (IIIb) tuted alkyl, aryl or substituted aryl; O R R2 O R3 R6 (0278 R is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, -l N R7 heteroalkyl, substituted heteroalkyl, heteroaryl, substituted X N N heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl: A 5 H R O R3 (0279 each R is independently selected from hydrogen, (Y), alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, sub stituted arylalkyl, heteroalkyl, substituted heteroalkyl, het eroaryl, substituted heteroaryl, heteroarylalkyl, and substi 0267 wherein tuted heteroarylalkyl: 0268 X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding 0280 b is a number from Zero to 100; and hydroxyl group of the enolic tautomer of the ketone is (0281) R' is selected from hydrogen, alkyl, substituted replaced by a covalent bond to —C(O)—N(A ring)-Y— alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted (CRR). NH C(O)-CH(R) N(R)-C(O)-CH alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi (R) N(R) R': tuted arylalkyl: 0269 the A ring is a heterocyclic 5 to 12-membered ring: 0282 or a salt, hydrate or solvate thereof. 0270 each Y is independently selected from alkyl, substi 0283. The present embodiments provide a compound of tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted formula IV:

(IV)

alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car 0284 wherein boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa (0285) R' is hydrogen or hydroxyl: cyl. Substituted aminoacyl, amino, Substituted amino, acy (0286) R' is hydrogen or alkyl: lamino, Substituted acylamino, and cyano; 0287 the A ring is a heterocyclic 5 to 12-membered ring: 0271 c is a number from Zero to 3: 0288 each Y is independently selected from alkyl, substi 0272 each R" is independently selected from hydrogen, tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car substituted alkynyl, aryl, substituted aryl, acyl, substituted boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, cyl. Substituted aminoacyl, amino, Substituted amino, acy aminoacyl, Substituted aminoacyl, amino, Substituted amino, lamino, Substituted acylamino, and cyano; acylamino, Substituted acylamino, and cyano; 0289 c is a number from Zero to 3: (0273 each R is independently selected from hydrogen, (0290 each R" is independently selected from hydrogen, alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoacyl, Substituted aminoacyl, amino, Substituted amino, aminoacyl, Substituted aminoacyl, amino, Substituted amino, acylamino, Substituted acylamino, and cyano; or acylamino, Substituted acylamino, and cyano; 0274 RandR together with the carbon to which they are 0291 each R is independently selected from hydrogen, attached can form a cycloalkyl or Substituted cycloalkyl alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, US 2014/O121 152 A1 May 1, 2014 substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoacyl, Substituted aminoacyl, amino, Substituted amino, aminoacyl, Substituted aminoacyl, amino, Substituted amino, acylamino, Substituted acylamino, and cyano; or acylamino, Substituted acylamino, and cyano; or (0309 RandR together with the carbon to which they are 0292 RandR together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl attached can form a cycloalkyl or substituted cycloalkyl group, or two R' or R groups on adjacent carbon atoms, group, or two R' or R groups on adjacent carbon atoms, together with the carbonatoms to which they are attached, can together with the carbonatoms to which they are attached, can form a cycloalkyl or Substituted cycloalkyl group; form a cycloalkyl or Substituted cycloalkyl group; 0310 a is an integer from one to 8: 0293 a is an integer from one to 8: 0311 provided that when a is one, the A ring is a hetero 0294 provided that when a is one, the A ring is a hetero cyclic 6 to 12-membered ring; and when the A ring is a cyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to heterocyclic 5-membered ring, then a is an integer from 2 to 8: 8: 0312 each R is independently hydrogen, alkyl, substi 0295 each R is independently hydrogen, alkyl, substi tuted alkyl, aryl or substituted aryl; tuted alkylaryl or substituted aryl; 0313 R is a side chain of an amino acid selected from 0296 R is selected from hydrogen, alkyl, substituted alanine, arginine, asparagine, aspartic acid, cysteine, alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, glutamic acid, glutamine, glycine, histidine, isoleucine, leu heteroalkyl, substituted heteroalkyl, heteroaryl, substituted cine, lysine, methionine, phenylalanine, proline, serine, heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl: threonine, tryptophan, tyrosine, Valine, homoarginine, 0297 each R is independently selected from hydrogen, homolysine, ornithine, arginine mimic, arginine homologue, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, sub arginine truncate, arginine with varying oxidation states, stituted arylalkyl, heteroalkyl, substituted heteroalkyl, het lysine mimic, lysine homologue, lysine truncate, and lysine eroaryl, substituted heteroaryl, heteroarylalkyl, and substi with varying oxidation states; tuted heteroarylalkyl: 0314 each R is a side chain of an amino acid indepen 0298 b is a number from Zero to 100; and dently selected from alanine, arginine, asparagine, aspartic 0299 R7 is selected from hydrogen, alkyl, substituted acid, cysteine, glutamic acid, glutamine, glycine, histidine, alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted isoleucine, leucine, lysine, methionine, phenylalanine, pro alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi line, serine, threonine, tryptophan, tyrosine and valine; tuted arylalkyl: 0315 b is a number from Zero to 100: 0300 or a salt, hydrate or solvate thereof. 0316 R7 is selected from hydrogen, alkyl, substituted 0301 The present embodiments provide a compound of alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted formula Va: alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi tuted arylalkyl: 0317 or a salt, hydrate or solvate thereof. (Va) 0318. The present embodiments provide a compound of O R R2 O R3 R6 formula Vb: -l N R7 X N N (Vb) A H R5 O RJ, O R R2 O R3 R6 (Y), -l N R7 X N N 0302 wherein A 0303 X represents a residue of a ketone-containing active H R5 O RJ, agent, wherein the hydrogen atom of the corresponding (Y), hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to C(O)N(A ring)-Y— (CRR). NH C(O)-CH(R) N(R)-C(O) CH 0319 wherein (R) N(R) R': 0320 X represents a residue of a ketone-containing 0304 the A ring is a heterocyclic 5 to 12-membered ring: opioid, wherein the hydrogen atom of the corresponding 0305 each Y is independently selected from alkyl, substi hydroxyl group of the enolic tautomer of the ketone is tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted replaced by a covalent bond to C(O)N(A ring)-Y— alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car (CRR). NH C(O)-CH(R) N(R)-C(O) CH boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa (R) N(R) R': cyl. Substituted aminoacyl, amino, Substituted amino, acy 0321 the A ring is a heterocyclic 5 to 12-membered ring: lamino, Substituted acylamino, and cyano; 0322 each Y is independently selected from alkyl, substi 0306 c is a number from Zero to 3: tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted (0307 each R" is independently selected from hydrogen, alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa substituted alkynyl, aryl, substituted aryl, acyl, substituted cyl. Substituted aminoacyl, amino, Substituted amino, acy acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, lamino, Substituted acylamino, and cyano; aminoacyl, Substituted aminoacyl, amino, Substituted amino, 0323 c is a number from Zero to 3: acylamino, Substituted acylamino, and cyano; 0324) each R" is independently selected from hydrogen, (0308) each R is independently selected from hydrogen, alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, US 2014/O121 152 A1 May 1, 2014

aminoacyl, Substituted aminoacyl, amino, Substituted amino, 0340 c is a number from Zero to 3: acylamino, Substituted acylamino, and cyano; 0341 each R" is independently selected from hydrogen, 0325 each R is independently selected from hydrogen, alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoacyl, Substituted aminoacyl, amino, Substituted amino, aminoacyl, Substituted aminoacyl, amino, Substituted amino, acylamino, Substituted acylamino, and cyano; acylamino, Substituted acylamino, and cyano; or (0342 each R is independently selected from hydrogen, alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, 0326) R' and R together with the carbon to which they are substituted alkynyl, aryl, substituted aryl, acyl, substituted attached can form a cycloalkyl or substituted cycloalkyl acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, group, or two R' or R groups on adjacent carbon atoms, aminoacyl, Substituted aminoacyl, amino, Substituted amino, together with the carbonatoms to which they are attached, can acylamino, Substituted acylamino, and cyano; or form a cycloalkyl or Substituted cycloalkyl group; (0343 R' and R together with the carbon to which they are 0327 a is an integer from one to 8: attached can form a cycloalkyl or substituted cycloalkyl 0328 provided that when a is one, the A ring is a hetero group, or two R' or R groups on adjacent carbon atoms, cyclic 6 to 12-membered ring; and when the A ring is a together with the carbonatoms to which they are attached, can heterocyclic 5-membered ring, then a is an integer from 2 to form a cycloalkyl or Substituted cycloalkyl group; 8: 0344 a is an integer from one to 8: 0329 each R is independently hydrogen, alkyl, substi 0345 provided that when a is one, the A ring is a hetero tuted alkyl, aryl or substituted aryl; cyclic 6 to 12-membered ring; and when the A ring is a 0330 R is a side chain of an amino acid selected from heterocyclic 5-membered ring, then a is an integer from 2 to alanine, arginine, asparagine, aspartic acid, cysteine, 8: glutamic acid, glutamine, glycine, histidine, isoleucine, leu (0346) each R is independently hydrogen, alkyl, substi cine, lysine, methionine, phenylalanine, proline, serine, tuted alkyl, aryl or substituted aryl; threonine, tryptophan, tyrosine, Valine, homoarginine, (0347 R represents a side chain of an amino acid, a side homolysine, ornithine, arginine mimic, arginine homologue, chain of an amino acid variant, a derivative of a side chain of arginine truncate, arginine with varying oxidation states, an amino acid, or a derivative of a side chain of an amino acid lysine mimic, lysine homologue, lysine truncate, and lysine variant that effects - C(O)-CH(R) N(R) to be a GI with varying oxidation states; enzyme-cleavable moiety; 0331 each R is a side chain of an amino acid indepen (0348 each R represents a side chain of an amino acid dently selected from alanine, arginine, asparagine, aspartic independently selected from alanine, arginine, asparagine, acid, cysteine, glutamic acid, glutamine, glycine, histidine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, isoleucine, leucine, lysine, methionine, phenylalanine, pro histidine, isoleucine, leucine, lysine, methionine, phenylala line, serine, threonine, tryptophan, tyrosine and valine; nine, proline, serine, threonine, tryptophan, tyrosine and 0332 b is a number from Zero to 100: Valine; 0333 R’ is selected from hydrogen, alkyl, substituted 0349 b is a number from Zero to 100: alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted 0350 R is selected from hydrogen, alkyl, substituted alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted tuted arylalkyl: alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi tuted arylalkyl: 0334 or a salt, hydrate or solvate thereof. 0351 or a salt, hydrate or solvate thereof. 0335 The present embodiments provide a compound of 0352. The present embodiments provide a compound of formula VIa: formula VIb:

(VIb) O R R2 O R3 R6 N X N

A H R5 O R3 (Y),

0336 wherein 0353 wherein 0337 X represents a residue of a ketone-containing active 0354 X represents a residue of a ketone-containing agent, wherein the hydrogen atom of the corresponding opioid, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to C(O)N(A ring)-Y— replaced by a covalent bond to C(O)N(A ring)-Y— (CRR). NH CO) CH(R) N(R) C(O)I. CH (CRR). NH C(O)-CH(R) N(R)-C(O) CH (R) N(R) R7: (R) N(R) R7: 0338 the A ring is a heterocyclic 5 to 12-membered ring: 0355 the A ring is a heterocyclic 5 to 12-membered ring: 0339 each Y is independently selected from alkyl, substi 0356 each Y is independently selected from alkyl, substi tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa cyl. Substituted aminoacyl, amino, Substituted amino, acy cyl. Substituted aminoacyl, amino, Substituted amino, acy lamino, Substituted acylamino, and cyano; lamino, Substituted acylamino, and cyano; US 2014/O121 152 A1 May 1, 2014

0357 c is a number from Zero to 3: 0369. In formula III and V-VI, X can be a residue of a 0358 each R" is independently selected from hydrogen, ketone-containing active agent oraketone-containing opioid. alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, 0370. In certain embodiments, the ketone-containing substituted alkynyl, aryl, substituted aryl, acyl, substituted active agent is a ketone-containing opioid. A ketone-con acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, taining opioid refers to a Subset of the opioids that contain a ketone group. As used herein, a ketone-containing opioid is aminoacyl, Substituted aminoacyl, amino, Substituted amino, an opioid containing an enolizable ketone group. A ketone acylamino, Substituted acylamino, and cyano; containing opioid is a compound with a pharmacophore that 0359 each R is independently selected from hydrogen, presents to the opioid receptor an aromatic group and an alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, aliphatic amine group in an architecturally discrete way. See, substituted alkynyl, aryl, substituted aryl, acyl, substituted for example, Foye's Principles of Medicinal Chemistry, Sixth acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, Edition, ed. T. L. Lemke and D. A. Williams, Lippincott aminoacyl, Substituted aminoacyl, amino, Substituted amino, Williams & Wilkins, 2008, particularly Chapter 24, pages acylamino, Substituted acylamino, and cyano; or 653-678. 0360 RandR together with the carbon to which they are 0371 For example, ketone-containing opioids include, attached can form a cycloalkyl or substituted cycloalkyl but are not limited to, acetylmorphone, hydrocodone, hydro group, or two R' or R groups on adjacent carbon atoms, morphone, ketobemidone, methadone, naloxone, naltrexone, together with the carbonatoms to which they are attached, can N-methylmaloxone, N-methylmaltrexone, oxycodone, oxy form a cycloalkyl or Substituted cycloalkyl group; morphone, and pentamorphone. 0361 a is an integer from one to 8: 0372. In certain embodiments, the ketone-containing 0362 provided that when a is one, the A ring is a hetero opioid is hydrocodone, hydromorphone, oxycodone, or oxy cyclic 6 to 12-membered ring; and when the A ring is a morphone. heterocyclic 5-membered ring, then a is an integer from 2 to 0373) In certain embodiments, the ketone-containing 8: opioid is naloxone, naltrexone, N-methylnaloxone, or N-me 0363 each R is independently hydrogen, alkyl, substi thylmaltrexone. tuted alkyl, aryl or substituted aryl; 0374. In certain embodiments, the ketone-containing 0364) R' represents a side chain of an amino acid, a side opioid is hydrocodone or oxycodone. In certain embodi chain of an amino acid variant, a derivative of a side chain of ments, the ketone-containing opioid is hydrocodone. In cer an amino acid, or a derivative of a side chain of an amino acid tain embodiments, the ketone-containing opioid is oxyc variant that effects –C(O)-CH(R) N(R)- to be a GI odone. enzyme-cleavable moiety; 0375. It is contemplated that opioids bearing at least some 0365 each R represents a side chain of an amino acid of the functionalities described herein will be developed; such independently selected from alanine, arginine, asparagine, opioids are included as part of the scope of this disclosure. aspartic acid, cysteine, glutamic acid, glutamine, glycine, 0376. In formula IV. R' can be hydrogen or hydroxyl. In histidine, isoleucine, leucine, lysine, methionine, phenylala certain instances, R is hydrogen. In other instances, R is nine, proline, serine, threonine, tryptophan, tyrosine and hydroxyl. Valine; 0377. In formula IV, R is hydrogen or alkyl. In certain 0366 b is a number from Zero to 100: instances, R is hydrogen. In other instances, R is alkyl. 0367 R’ is selected from hydrogen, alkyl, substituted 0378 Particular compounds of interest, and salts or sol alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted vates or stereoisomers thereof, include: alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi 0379 N-(oxycodone-6-enol-carbonyl)-R-(piperidine-2- tuted arylalkyl: methylamine)-L-arginine-glycine-malonate (Compound 0368 or a salt, hydrate or solvate thereof. KC-17):

O O O US 2014/O121 152 A1 May 1, 2014 19

0380 N-(oxycodone-6-enol-carbonyl)piperidine-2-me- 0382 N-(oxycodone-6-enol-carbonyl)piperidine-2-me thylamine-L-arginine-malonate (Compound KC-12): thylamine-L-arginine-glycine-acetate (Compound KC-14):

-CH N OH O N Ruson1. ( )NOs ) O O HC-O O N NH O O

H2 -l NH O NH NSI H s 0381, N-(oxycodone-6-enol-carbonyl)piperidine-2-me- NH thylamine-L-arginine-L-alanine-acetate (Compound l KC-13): H.N. N

0383 N-(oxycodone-6-enol-carbonyl)piperidine-2-me thylamine-L-arginine-L-alanine-malonate (Compound O lsO KC-15):

H.N. N

N

NH

HN N US 2014/O121 152 A1 May 1, 2014 20

0384 N-(oxycodone-6-enol-carbonyl)piperidine-2-me thylamine-L-arginine-glycine-malonate (Compound KC-16):

O O O

N N O

NH

HN N and 0385 N-(hydrocodone-6-enol-carbonyl)-R-(piperidine 2-methylamine)-L-arginine-glycine-malonate (Compound KC-31): CH

- 3

O O O r s N N O H

HN N

0386 Particular compounds of interest, and salts or sol vates or stereoisomers thereof, include: (0387 Compound KC-32:

N C O OH

- O O O. N. O O O - NNH N-r H s O NH

HN l N 2 H US 2014/O121 152 A1 May 1, 2014 21

0388 Compound KC-35:

N )--> (O r O E O O

NNH 1sH OH O

HN N

0389 Compound KC-36: 0391 Compound KC-38:

N N

- O O N O O O {{ r i ls - OSY O to O O NN N NH H l O H2N N NH H l HN N 2 H 0390 Compound KC-37: 0392 Compound KC-39: 3

O. toN. O E O ( )N ) E H : O O n N - O O N NH 1NH s O H O O R N NH n

H2 -- H US 2014/O121 152 A1 May 1, 2014 22

0393 Compound KC-40: 0396 Compound KC-43:

O N O H O < N ls N 1N O N NH O

H.N.l N. O H NH Y O

HN N 0394 Compound KC-41:

O ( ) () o1 0397) Compound KC-44:

NH l N --~O - O XSO XO N > 0395 Compound KC-42: y O O N H r" O O r HN N O 3. H r’sO HN J. US 2014/O121 152 A1 May 1, 2014 23

0398 Compound KC-45:

N

2 - O XXO O N--> O O O O NH ulus NH sH OH: O

HN N

0399 Compound KC-46: 04.01 Compound KC-48: \ \ N O

O - O 2 O N N1 ( ) \) is OH O O O O NH ls o O O N O

O O N NH

HN l N 2 H

(0400 Compound KC-47:

OH

N N O US 2014/O121 152 A1 May 1, 2014 24

0402 Compound KC-49: (0404 Compound KC-51:

N N

( ) ( ) O OH ( ) ( ) O OH - O 4. O N - O a O N

O O N 1 NH N O O NH ls HN HN N

0403. Compound KC-50: 04.05 Compound KC-52:

V N N

OH ( ) \)2 O OH { 4. O -O O O N - O O N O H O N ls O N OH: O O O

HN HN

(0406 Compound KC-53:

HN US 2014/O121 152 A1 May 1, 2014 25 and 0412 wherein 04.07 Compound KC-55: 0413 X represents a residue of a phenolic active agent, wherein the hydrogenatom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O) NI (A ring)-Y— V (CRR). NH CO) CH(R) N(R) C(O) CH N (R) N(R) R': OH 0414 the A ring is a heterocyclic 5 to 12-membered ring: 0415 each Y is independently selected from alkyl, substi tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car ( ) \)2 O OH boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa -O O O N cyl. Substituted aminoacyl, amino, Substituted amino, acy Y H O lamino, Substituted acylamino, and cyano; O N ls 0416 c is a number from Zero to 3: NN11N N 10417 each R" is independently selected from hydrogen, O alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, H.N. N aminoacyl, Substituted aminoacyl, amino, Substituted amino, acylamino, Substituted acylamino, and cyano; 0418 each R is independently selected from hydrogen, alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, Phenolic Active Agent Prodrugs substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, 0408. The disclosure provides a phenolic active agent pro aminoacyl, Substituted aminoacyl, amino, Substituted amino, drug that provides controlled release of a phenolic active acylamino, Substituted acylamino, and cyano; or agent. In a phenolic active agent prodrug, a promoiety is 0419 RandR together with the carbon to which they are attached to the phenolic active agent through the phenolic attached can form a cycloalkyl or Substituted cycloalkyl oxygen atom. In a phenolic active agent prodrug, the oxygen group, or two R' or R groups on adjacent carbon atoms, atom of the phenol group of the phenolic active agent is together with the carbonatoms to which they are attached, can replaced by a covalent bond to a promoiety. form a cycloalkyl or substituted cycloalkyl group; 04.09. As disclosed herein, an enzyme-cleavable phenolic 0420 a is an integer from one to 8: active agent prodrug is a phenolic active agent prodrug that 0421 provided that when a is one, the A ring is a hetero comprises a promoiety comprising an enzyme-cleavable cyclic 6 to 12-membered ring; and when the A ring is a moiety, i.e., a moiety having a site Susceptible to cleavage by heterocyclic 5-membered ring, then a is an integer from 2 to an enzyme. In one embodiment, the cleavable moiety is a GI 8: enzyme-cleavable moiety, such as a trypsin-cleavable moiety. 0422 each R is independently hydrogen, alkyl, substi Such a prodrug comprises a phenolic active agent covalently tuted alkyl, aryl or substituted aryl; bound to a promoiety comprising an enzyme-cleavable moi 0423 R is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, ety, wherein cleavage of the enzyme-cleavable moiety by an heteroalkyl, substituted heteroalkyl, heteroaryl, substituted enzyme mediates release of the drug. heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl: 0424 each R is independently selected from hydrogen, Formulae VII-X alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, sub 0410 Compounds of the present disclosure include com stituted arylalkyl, heteroalkyl, substituted heteroalkyl, het pounds of formulae VII-X shown below. Compositions of the eroaryl, substituted heteroaryl, heteroarylalkyl, and substi present disclosure also include compounds of formulae VII-X tuted heteroarylalkyl: shown below. Pharmaceutical compositions and methods of 0425 b is a number from Zero to 100: the present disclosure also contemplate compounds of formu 0426) R' is selected from hydrogen, alkyl, substituted lae VII-X. Reference to the formula number is meant to alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted include compounds of both the “a” and “b' versions of the alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi formula number. tuted arylalkyl: 0411. The present embodiments provide a compound of 0427 or a salt, hydrate or solvate thereof. formula VIIa: 0428 The present embodiments provide a compound of formula VIIb:

(VIIa) (VIIb) R1 R2 O R3 6 O R 7 O R1 R2 O R3 R6 R X ul-X.N N N N ls a NN N R7 X N N A H R5 3 A O RJ, H R5 O R3 (Y), (Y), US 2014/O121 152 A1 May 1, 2014 26

0429 wherein 0445. The present embodiments provide a compound of 0430 X represents a residue of a phenolic opioid, wherein formula VIII: the hydrogenatom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O) N (A ring)-Y. (CRR) (VIII) NH C(O)-CH(R) N(R)-C(O)-CH(R) N (R) R7: 0431 the A ring is a heterocyclic 5 to 12-membered ring; 0432 each Y is independently selected from alkyl, substi tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa cyl. Substituted aminoacyl, amino, Substituted amino, acy lamino, Substituted acylamino, and cyano; 0433 c is a number from Zero to 3: 0446 wherein 0434 each R" is independently selected from hydrogen, 0447 R is hydrogen or hydroxyl: alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, I0448) R' is hydrogen or alkyl; 0449 the A ring is a heterocyclic 5 to 12-membered ring: substituted alkynyl, aryl, substituted aryl, acyl, substituted 0450 each Y is independently selected from alkyl, substi acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted aminoacyl, Substituted aminoacyl, amino, Substituted amino, alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car acylamino, Substituted acylamino, and cyano; boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, acy lamino, Substituted acylamino, Substituted aminoacyl, amino, 0435 each R is independently selected from hydrogen, Substituted amino, acylamino, and cyano; alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, 0451 c is a number from Zero to 3: 0452 each R" is independently selected from hydrogen, substituted alkynyl, aryl, substituted aryl, acyl, substituted alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted aminoacyl, Substituted aminoacyl, amino, Substituted amino, acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, acylamino, Substituted acylamino, and cyano; or aminoacyl, Substituted aminoacyl, amino, Substituted amino, acylamino, Substituted acylamino, and cyano; 0436 RandR together with the carbon to which they are 0453 each R is independently selected from hydrogen, attached can form a cycloalkyl or Substituted cycloalkyl alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, group, or two R' or R groups on adjacent carbon atoms, substituted alkynyl, aryl, substituted aryl, acyl, substituted together with the carbonatoms to which they are attached, can acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, form a cycloalkyl or Substituted cycloalkyl group; aminoacyl, Substituted aminoacyl, amino, Substituted amino, acylamino, Substituted acylamino, and cyano; or 0437 a is an integer from one to 8: 0454) R' and R together with the carbon to which they are attached can form a cycloalkyl or Substituted cycloalkyl 0438 provided that when a is one, the A ring is a hetero group, or two R' or R groups on adjacent carbon atoms, cyclic 6 to 12-membered ring; and when the A ring is a together with the carbonatoms to which they are attached, can heterocyclic 5-membered ring, then a is an integer from 2 to form a cycloalkyl or Substituted cycloalkyl group; 8: 0455 a is an integer from one to 8: 0439 each R is independently hydrogen, alkyl, substi 0456 provided that when a is one, the A ring is a hetero cyclic 6 to 12-membered ring; and when the A ring is a tuted alkyl, aryl or substituted aryl; heterocyclic 5-membered ring, then a is an integer from 2 to 0440 R is selected from hydrogen, alkyl, substituted 8: alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, 0457 each R is independently hydrogen, alkyl, substi heteroalkyl, substituted heteroalkyl, heteroaryl, substituted tuted alkyl, aryl or substituted aryl; heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl: 0458 R is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, 0441 each R is independently selected from hydrogen, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, sub heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl: stituted arylalkyl, heteroalkyl, substituted heteroalkyl, het 10459 each R is independently selected from hydrogen, eroaryl, substituted heteroaryl, heteroarylalkyl, and substi alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, sub tuted heteroarylalkyl: stituted arylalkyl, heteroalkyl, substituted heteroalkyl, het eroaryl, substituted heteroaryl, heteroarylalkyl, and substi 0442 b is a number from Zero to 100: tuted heteroarylalkyl: 0443) R' is selected from hydrogen, alkyl, substituted 0460 b is a number from Zero to 100: alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted 0461) R' is selected from hydrogen, alkyl, substituted alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi tuted arylalkyl: tuted arylalkyl: 0444 or a salt, hydrate or solvate thereof. 0462 or a salt, hydrate or solvate thereof. US 2014/O121 152 A1 May 1, 2014 27

0463. The present embodiments provide a compound of isoleucine, leucine, lysine, methionine, phenylalanine, pro formula IXa: line, serine, threonine, tryptophan, tyrosine and valine; 0477 b is a number from Zero to 100: 0478 R7 is selected from hydrogen, alkyl, substituted (IXa) alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi O R1 R2 O R3 R6 tuted arylalkyl: ls N R7 0479 or a salt, hydrate or solvate thereof. X N an N N 0480. The present embodiments provide a compound of A formula IXb: H R5 O RJ, (Y), (IXb) 0464 wherein O R1 R2 O R3 R6 0465 X represents a residue of a phenolic active agent, wherein the hydrogenatom of the phenolic hydroxyl group is ls N R7 X N N N replaced by a covalent bond to —C(O)—N(A ring)-Y— A 5 (CRR). NH CO) CH(R) N(R) C(O) CH H R O R3 (R) N(R) R': (Y), 0466 the A ring is a heterocyclic 5 to 12-membered ring: 0467 each Y is independently selected from alkyl, substi tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted 0481 wherein alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car 0482 X represents a residue of a phenolic opioid, wherein boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa the hydrogenatom of the phenolic hydroxyl group is replaced cyl. Substituted aminoacyl, amino, Substituted amino, acy by a covalent bond to —C(O) N (A ring)-Y. (CRR) lamino, Substituted acylamino, and cyano; NH C(O) CH(R) N(R) C(O) CH(R) N (R) R': 0468 c is a number from Zero to 3: 0483 the A ring is a heterocyclic 5 to 12-membered ring: 0469 each R" is independently selected from hydrogen, 0484 each Y is independently selected from alkyl, substi alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted substituted alkynyl, aryl, substituted aryl, acyl, substituted alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa aminoacyl, Substituted aminoacyl, amino, Substituted amino, cyl. Substituted aminoacyl, amino, Substituted amino, acy acylamino, Substituted acylamino, and cyano; lamino, Substituted acylamino, and cyano; 0470 each R is independently selected from hydrogen, 0485 c is a number from Zero to 3: alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, 0486 each R" is independently selected from hydrogen, substituted alkynyl, aryl, substituted aryl, acyl, substituted alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted aminoacyl, Substituted aminoacyl, amino, Substituted amino, acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, acylamino, Substituted acylamino, and cyano; or aminoacyl, Substituted aminoacyl, amino, Substituted amino, 0471) R' and R together with the carbon to which they are acylamino, Substituted acylamino, and cyano; attached can form a cycloalkyl or Substituted cycloalkyl 0487 each R is independently selected from hydrogen, group, or two R' or R groups on adjacent carbon atoms, alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, together with the carbonatoms to which they are attached, can substituted alkynyl, aryl, substituted aryl, acyl, substituted form a cycloalkyl or Substituted cycloalkyl group; acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, 0472 a is an integer from one to 8: aminoacyl, Substituted aminoacyl, amino, Substituted amino, 0473 provided that when a is one, the A ring is a hetero acylamino, Substituted acylamino, and cyano; or cyclic 6 to 12-membered ring; and when the A ring is a 0488 RandR together with the carbon to which they are heterocyclic 5-membered ring, then a is an integer from 2 to attached can form a cycloalkyl or Substituted cycloalkyl 8: group, or two R' or R groups on adjacent carbon atoms, 0474 each R is independently hydrogen, alkyl, substi together with the carbonatoms to which they are attached, can tuted alkyl, aryl or substituted aryl; form a cycloalkyl or Substituted cycloalkyl group; 0475 R is a side chain of an amino acid selected from 0489 a is an integer from one to 8: alanine, arginine, asparagine, aspartic acid, cysteine, 0490 provided that when a is one, the A ring is a hetero glutamic acid, glutamine, glycine, histidine, isoleucine, leu cyclic 6 to 12-membered ring; and when the A ring is a cine, lysine, methionine, phenylalanine, proline, serine, heterocyclic 5-membered ring, then a is an integer from 2 to threonine, tryptophan, tyrosine, Valine, homoarginine, 8: homolysine, ornithine, arginine mimic, arginine homologue, 0491 each R is independently hydrogen, alkyl, substi arginine truncate, arginine with varying oxidation states, tuted alkyl, aryl or substituted aryl; lysine mimic, lysine homologue, lysine truncate, and lysine 0492 R is a side chain of an amino acid selected from with varying oxidation states; alanine, arginine, asparagine, aspartic acid, cysteine, 0476) each R is a side chain of an amino acid indepen glutamic acid, glutamine, glycine, histidine, isoleucine, leu dently selected from alanine, arginine, asparagine, aspartic cine, lysine, methionine, phenylalanine, proline, serine, acid, cysteine, glutamic acid, glutamine, glycine, histidine, threonine, tryptophan, tyrosine, Valine, homoarginine, US 2014/O121 152 A1 May 1, 2014 28 homolysine, ornithine, arginine mimic, arginine homologue, (0508) each R is independently hydrogen, alkyl, substi arginine truncate, arginine with varying oxidation states, tuted alkyl, aryl or substituted aryl; lysine mimic, lysine homologue, lysine truncate, and lysine (0509 R represents a side chain of an amino acid, a side with varying oxidation states; chain of an amino acid variant, a derivative of a side chain of 0493 each R is a side chain of an amino acid indepen an amino acid, or a derivative of a side chain of an amino acid dently selected from alanine, arginine, asparagine, aspartic variant that effects - C(O)-CH(R) N(R) to be a GI acid, cysteine, glutamic acid, glutamine, glycine, histidine, enzyme-cleavable moiety; isoleucine, leucine, lysine, methionine, phenylalanine, pro 10510) each R represents a side chain of an amino acid line, serine, threonine, tryptophan, tyrosine and valine; independently selected from alanine, arginine, asparagine, 0494 b is a number from Zero to 100: aspartic acid, cysteine, glutamic acid, glutamine, glycine, 0495 R7 is selected from hydrogen, alkyl, substituted histidine, isoleucine, leucine, lysine, methionine, phenylala alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted nine, proline, serine, threonine, tryptophan, tyrosine and alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi Valine; tuted arylalkyl: 0511 b is a number from Zero to 100: 0496 or a salt, hydrate or solvate thereof. (0512 R is selected from hydrogen, alkyl, substituted 0497. The present embodiments provide a compound of alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted formula Xa: alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi tuted arylalkyl: 0513 or a salt, hydrate or solvate thereof. (Xa) 0514. The present embodiments provide a compound of formula Xb: O R R2 O R3 R6 -l N R7 x - is (Xb) A H R5 O R O R! R2 R3 R6 (Y), x -- 0498 wherein A. H R5 O RJ, 0499 X represents a residue of a phenolic active agent, wherein the hydrogenatom of the phenolic hydroxyl group is (Y), replaced by a covalent bond to —C(O) N(A ring)-Y- (CRR). NH CO) CH(R) N(R) C(O) CH 0515 wherein (R) N(R) R7: 0516 X represents a residue of a phenolic opioid, wherein 0500 the A ring is a heterocyclic 5 to 12-membered ring: the hydrogenatom of the phenolic hydroxyl group is replaced 0501 each Y is independently selected from alkyl, substi by a covalent bond to —C(O) N (A ring)-Y. (CRR) tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted NH C(O)-CH(R) N(R)-C(O)-CH(R) N alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car (R) R': boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa 0517 the A ring is a heterocyclic 5 to 12-membered ring: cyl. Substituted aminoacyl, amino, Substituted amino, acy 0518 each Y is independently selected from alkyl, substi lamino, Substituted acylamino, and cyano; tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted 0502 c is a number from Zero to 3: alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car (0503 each R" is independently selected from hydrogen, boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, cyl. Substituted aminoacyl, amino, Substituted amino, acy substituted alkynyl, aryl, substituted aryl, acyl, substituted lamino, Substituted acylamino, and cyano; acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, 0519 c is a number from Zero to 3: aminoacyl, Substituted aminoacyl, amino, Substituted amino, (0520 each R" is independently selected from hydrogen, acylamino, Substituted acylamino, and cyano; alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, (0504 each R is independently selected from hydrogen, substituted alkynyl, aryl, substituted aryl, acyl, substituted alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted aminoacyl, Substituted aminoacyl, amino, Substituted amino, acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, acylamino, Substituted acylamino, and cyano; aminoacyl, Substituted aminoacyl, amino, Substituted amino, 0521 each R is independently selected from hydrogen, acylamino, Substituted acylamino, and cyano; or alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, 0505) R' and R together with the carbon to which they are substituted alkynyl, aryl, substituted aryl, acyl, substituted attached can form a cycloalkyl or Substituted cycloalkyl acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, group, or two R' or R groups on adjacent carbon atoms, aminoacyl, Substituted aminoacyl, amino, Substituted amino, together with the carbonatoms to which they are attached, can acylamino, Substituted acylamino, and cyano; or form a cycloalkyl or Substituted cycloalkyl group; 0522) R' and R together with the carbon to which they are 0506 a is an integer from one to 8: attached can form a cycloalkyl or Substituted cycloalkyl 0507 provided that when a is one, the A ring is a hetero group, or two R' or R groups on adjacent carbon atoms, cyclic 6 to 12-membered ring; and when the A ring is a together with the carbonatoms to which they are attached, can heterocyclic 5-membered ring, then a is an integer from 2 to form a cycloalkyl or Substituted cycloalkyl group; 8: 0523 a is an integer from one to 8: US 2014/O121 152 A1 May 1, 2014 29

0524 provided that when a is one, the A ring is a hetero 0540 Particular compound of interest, and salts or sol cyclic 6 to 12-membered ring; and when the A ring is a Vates or stereoisomers thereof, includes: heterocyclic 5-membered ring, then a is an integer from 2 to 0541 N-(Tapentadol-carbonyl)piperidine-2-methy 8: lamine-L-arginine-malonate (Compound TP-5): 0525 each R is independently hydrogen, alkyl, substi tuted alkyl, aryl or substituted aryl; 0526 R represents a side chain of an amino acid, a side chain of an amino acid variant, a derivative of a side chain of an amino acid, or a derivative of a side chain of an amino acid variant that effects - C(O) CH(R) N(R) to be a GI enzyme-cleavable moiety; 0527 each R represents a side chain of an amino acid independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylala nine, proline, serine, threonine, tryptophan, tyrosine and Valine; 0528 b is a number from Zero to 100: Amide-Modified Active Agent Prodrugs 0529) R' is selected from hydrogen, alkyl, substituted 0542. The disclosure provides an amide-modified active alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted agent prodrug that provides controlled release of an amide alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi containing active agent. As shown below, in an amide-modi tuted arylalkyl: fied active agent prodrug, a promoiety is attached to the 0530 or a salt, hydrate or solvate thereof. amide-containing active agent through the enolic oxygen 0531. In formula VII and IX-X, X can be a residue of a atom of the amide enol moiety or through the oxygen of the phenolic active agent or a phenolic opioid. imine tautomer. In an amide-modified active agent prodrug, 0532. In certain embodiments, the phenolic active agent is the hydrogen atom of the corresponding enolic group of the a phenolic opioid. A "phenolic opioid refers to a subset of the amide enol or of the imine tautomer of the amide-containing opioids that contain a phenol group. A phenolic opioid is a active agent is replaced by a covalent bond to a promoiety. In compound with a pharmacophore that presents to the opioid certain embodiments, the promoiety that replaces the hydro receptor an aromatic group and an aliphatic amine group in an gen atom of the corresponding enolic group of the amide enol architecturally discrete way. See, for example, Foye's Prin or the imine tautomer of the amide-containing active agent ciples of Medicinal Chemistry, Sixth Edition, ed. T. L. Lemke contains an acyl group as the point of connection. and D. A. Williams, Lippincott Williams & Wilkins, 2008, particularly Chapter 24, pages 653-678. 0533. For instance, the following opioids contain a phenol O R R2 O R3 R6 group that can be a point of attachment to a promoiety: o-l N R7 buprenorphine, dihydroetorphine, diprenorphine, etorphine, hydromorphone, levorphanol, morphine, nalbuphine, ls N A 5 3 nalmefene, nalorphine, naloxone, naltrexone, N-methyldi R NR H R O R prenorphine, N-methylnaloxone, N-methylmaltrexone, oripa (Y), vine, oxymorphone, butorphanol, dezocine, ketobemidone, meptazinol, o-desmethyltramadol, pentazocine, phenazo imine tautomer where Rand Rare collectively the rest of the amide-containing opioid or cine, and tapentadol. one of the RandR is hydrogen and the other is the rest is the amide 0534. In certain embodiments, the phenolic opioid is containing opioid hydromorphone, morphine, oxymorphone, or tapentadol. O R R2 O R3 R6 0535 In certain embodiments, the phenolic opioid is naloxone, naltrexone, N-methylnaloxone, or N-methylmaltr ls N R7 exone. In certain embodiments, the phenolic opioid is k > diprenorphine or N-methyldiprenorphine. 1. A H R5 O R3 0536. In certain embodiments, the phenolic opioid is R NRR" (Y), hydromorphone. In certain embodiments, the phenolic opioid is morphine. In certain embodiments, the phenolic opioid is amide enol oxymorphone. In certain embodiments, the phenolic opioidis where R, R', and R" are collectively the rest of the amide-containing opioid tapentadol. or at least one of R, R', and R" is hydrogen and the rest of R, R', and R" 0537. It is contemplated that opioids bearing at least some are collectively the rest of the amide-containing opioid of the functionalities described herein will be developed; such opioids are included as part of the scope of this disclosure. 0543. As disclosed herein, an enzyme-cleavable amide 0538 Informula VIII, R' can behydrogen or hydroxyl. In modified active agent prodrug is an amide-modified active certain instances, R is hydrogen. In other instances, R is agent prodrug that comprises a promoiety comprising an hydroxyl. enzyme-cleavable moiety, i.e., a moiety having a site Suscep 0539. In formula VIII, R is hydrogen or alkyl. In certain tible to cleavage by an enzyme. Release of the active agent is instances, R is hydrogen. In other instances, R is alkyl. mediated by enzymatic cleavage of the promoiety from the US 2014/O121 152 A1 May 1, 2014 30 amide-containing active agent. In one embodiment, the cleav (0556) each R is independently hydrogen, alkyl, substi able moiety is a GI enzyme-cleavable moiety, such as a tuted alkyl, aryl or substituted aryl; trypsin-cleavable moiety. 10557 R is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, Formulae XI-XIII heteroalkyl, substituted heteroalkyl, heteroaryl, substituted 0544 Compounds of the present disclosure include com heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl: pounds of formulae XI-XIII shown below. Compositions of 0558 each R is independently selected from hydrogen, the present disclosure also include compounds of formulae alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, sub XI-XIII shown below. Pharmaceutical compositions and stituted arylalkyl, heteroalkyl, substituted heteroalkyl, het methods of the present disclosure also contemplate com eroaryl, substituted heteroaryl, heteroarylalkyl, and substi pounds of formulae XI-XIII. Reference to the formula num tuted heteroarylalkyl: ber is meant to include compounds of both the “a” and “b' 0559 b is a number from Zero to 100: versions of the formula number. 10560) R' is selected from hydrogen, alkyl, substituted 0545. The present embodiments provide a compound of alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted formula XIa: alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi tuted arylalkyl: 0561 or a salt, hydrate or solvate thereof. (XIa) 0562. The present embodiments provide a compound of formula XIb: O R R2 O R3 R6 ls N R7 X N (XIb) A H R5 O RJ, O R R2 O R3 R6 (Y), X -l N N R7 A 0546 wherein H R5 O RJ, (0547 X represents a residue of an amide-containing active (Y). agent, wherein —C(O) N(A ring)-Y. (CRR) NH C(O) CH(R) N(R) C(O) CH(R) N(R) R is connected to the amide-containing active agent 0563 wherein through the oxygen of the amide group, wherein the amide 0564 X represents a residue of an amide-containing group is converted to an amide enol or an imine tautomer, opioid, wherein - C(O) N(A ring)-Y. (CRR) 0548 the A ring is a heterocyclic 5 to 12-membered ring: NH CO) CH(R) N(R) C(O) CH(R) N(R) 0549 each Y is independently selected from alkyl, substi R is connected to the amide-containing active agent tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted through the oxygen of the amide group, wherein the amide alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car group is converted to an amide enol or an imine tautomer, boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa 0565 the A ring is a heterocyclic 5 to 12-membered ring: cyl. Substituted aminoacyl, amino, Substituted amino, acy 0566 each Y is independently selected from alkyl, substi lamino, Substituted acylamino, and cyano; tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted 0550 c is a number from Zero to 3: alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car 0551 each R" is independently selected from hydrogen, boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, cyl. Substituted aminoacyl, amino, Substituted amino, acy substituted alkynyl, aryl, substituted aryl, acyl, substituted lamino, Substituted acylamino, and cyano; acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, 0567 c is a number from Zero to 3: aminoacyl, Substituted aminoacyl, amino, Substituted amino, 10568 each R" is independently selected from hydrogen, acylamino, Substituted acylamino, and cyano; alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, 0552 each R is independently selected from hydrogen, substituted alkynyl, aryl, substituted aryl, acyl, substituted alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted aminoacyl, Substituted aminoacyl, amino, Substituted amino, acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, acylamino, Substituted acylamino, and cyano; aminoacyl, Substituted aminoacyl, amino, Substituted amino, 0569 each R is independently selected from hydrogen, acylamino, Substituted acylamino, and cyano; or alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, 0553 R' and R together with the carbon to which they are substituted alkynyl, aryl, substituted aryl, acyl, substituted attached can form a cycloalkyl or Substituted cycloalkyl acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, group, or two R' or R groups on adjacent carbon atoms, aminoacyl, Substituted aminoacyl, amino, Substituted amino, together with the carbonatoms to which they are attached, can acylamino, Substituted acylamino, and cyano; or form a cycloalkyl or Substituted cycloalkyl group; 0570) R' and R together with the carbon to which they are 0554 a is an integer from one to 8: attached can form a cycloalkyl or Substituted cycloalkyl 0555 provided that when a is one, the A ring is a hetero group, or two R' or R groups on adjacent carbon atoms, cyclic 6 to 12-membered ring; and when the A ring is a together with the carbonatoms to which they are attached, can heterocyclic 5-membered ring, then a is an integer from 2 to form a cycloalkyl or Substituted cycloalkyl group; 8: 0571 a is an integer from one to 8: US 2014/O121 152 A1 May 1, 2014

0572 provided that when a is one, the A ring is a hetero together with the carbonatoms to which they are attached, can cyclic 6 to 12-membered ring; and when the A ring is a form a cycloalkyl or Substituted cycloalkyl group; heterocyclic 5-membered ring, then a is an integer from 2 to 0588 a is an integer from one to 8: 8: 0589 provided that when a is one, the A ring is a hetero (0573 each R is independently hydrogen, alkyl, substi cyclic 6 to 12-membered ring; and when the A ring is a tuted alkyl, aryl or substituted aryl; heterocyclic 5-membered ring, then a is an integer from 2 to (0574 R is selected from hydrogen, alkyl, substituted 8: alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, 0590 each R is independently hydrogen, alkyl, substi heteroalkyl, substituted heteroalkyl, heteroaryl, substituted tuted alkyl, aryl or substituted aryl; heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl: 0591) R' is a side chain of an amino acid selected from (0575 each R is independently selected from hydrogen, alanine, arginine, asparagine, aspartic acid, cysteine, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, sub glutamic acid, glutamine, glycine, histidine, isoleucine, leu stituted arylalkyl, heteroalkyl, substituted heteroalkyl, het cine, lysine, methionine, phenylalanine, proline, serine, eroaryl, substituted heteroaryl, heteroarylalkyl, and substi threonine, tryptophan, tyrosine, Valine, homoarginine, tuted heteroarylalkyl: homolysine, ornithine, arginine mimic, arginine homologue, 0576 b is a number from Zero to 100: arginine truncate, arginine with varying oxidation states, (0577 R’ is selected from hydrogen, alkyl, substituted lysine mimic, lysine homologue, lysine truncate, and lysine alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted with varying oxidation states; alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi 0592 each R is a side chain of an amino acid indepen tuted arylalkyl: dently selected from alanine, arginine, asparagine, aspartic 0578 or a salt, hydrate or solvate thereof. acid, cysteine, glutamic acid, glutamine, glycine, histidine, 0579. The present embodiments provide a compound of isoleucine, leucine, lysine, methionine, phenylalanine, pro formula XIIa: line, serine, threonine, tryptophan, tyrosine and valine; 0593 b is a number from Zero to 100: 0594) R' is selected from hydrogen, alkyl, substituted (XIIa) alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted O R R2 O R3 R6 alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi tuted arylalkyl: -l N R7 0595 or a salt, hydrate or solvate thereof. N 0596. The present embodiments provide a compound of A H R5 O RJ, formula XIIb: (Y), (XIIb) 0580 wherein 0581 X represents a residue of an amide-containing active O R1 R2 O R3 R6 agent, wherein –C(O) N (A ring)-Y. (CRR), -l N R7 NH C(O) CH(R) N(R) C(O) CH(R) N(R) X N R is connected to the amide-containing active agent through the oxygen of the amide group, wherein the amide A H R5 O RJ, group is converted to an amide enol or an imine tautomer, (Y), 0582 the A ring is a heterocyclic 5 to 12-membered ring: 0583 each Y is independently selected from alkyl, substi tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted 0597 wherein alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car 0598 X represents a residue of an amide-containing boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa opioid, wherein - C(O) N (A ring)-Y. (CRR), cyl. Substituted aminoacyl, amino, Substituted amino, acy NH CO) CH(R) N(R) C(O) CH(R) N(R) lamino, Substituted acylamino, and cyano; R is connected to the amide-containing active agent 0584 c is a number from Zero to 3: through the oxygen of the amide group, wherein the amide 0585 each R" is independently selected from hydrogen, group is converted to an amide enol or an imine tautomer, alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, 0599 the A ring is a heterocyclic 5 to 12-membered ring: substituted alkynyl, aryl, substituted aryl, acyl, substituted 0600 each Y is independently selected from alkyl, substi acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted aminoacyl, Substituted aminoacyl, amino, Substituted amino, alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car acylamino, Substituted acylamino, and cyano; boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa 0586) each R is independently selected from hydrogen, cyl. Substituted aminoacyl, amino, Substituted amino, acy alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, lamino, Substituted acylamino, and cyano; substituted alkynyl, aryl, substituted aryl, acyl, substituted 0601 c is a number from Zero to 3: acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, (0602 each R" is independently selected from hydrogen, aminoacyl, Substituted aminoacyl, amino, Substituted amino, alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, acylamino, Substituted acylamino, and cyano; or substituted alkynyl, aryl, substituted aryl, acyl, substituted 0587 RandR together with the carbon to which they are acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, attached can form a cycloalkyl or Substituted cycloalkyl aminoacyl, Substituted aminoacyl, amino, Substituted amino, group, or two R' or R groups on adjacent carbon atoms, acylamino, Substituted acylamino, and cyano; US 2014/O121 152 A1 May 1, 2014 32

0603 each R is independently selected from hydrogen, cyl. Substituted aminoacyl, amino, Substituted amino, acy alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, lamino, Substituted acylamino, and cyano; substituted alkynyl, aryl, substituted aryl, acyl, substituted 0618 c is a number from Zero to 3: acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, 0619 each R" is independently selected from hydrogen, aminoacyl, Substituted aminoacyl, amino, Substituted amino, alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, acylamino, Substituted acylamino, and cyano; or substituted alkynyl, aryl, substituted aryl, acyl, substituted 0604) R' and R together with the carbon to which they are acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, attached can form a cycloalkyl or Substituted cycloalkyl aminoacyl, Substituted aminoacyl, amino, Substituted amino, group, or two R' or R groups on adjacent carbon atoms, acylamino, Substituted acylamino, and cyano; together with the carbonatoms to which they are attached, can (0620 each R is independently selected from hydrogen, form a cycloalkyl or Substituted cycloalkyl group; alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, 0605 a is an integer from one to 8: substituted alkynyl, aryl, substituted aryl, acyl, substituted 0606 provided that when a is one, the A ring is a hetero acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, cyclic 6 to 12-membered ring; and when the A ring is a aminoacyl, Substituted aminoacyl, amino, Substituted amino, heterocyclic 5-membered ring, then a is an integer from 2 to acylamino, Substituted acylamino, and cyano; or 8: 0621) R' and R together with the carbon to which they are 0607 each R is independently hydrogen, alkyl, substi attached can form a cycloalkyl or Substituted cycloalkyl tuted alkyl, aryl or substituted aryl; group, or two R' or R groups on adjacent carbon atoms, 0608 R is a side chain of an amino acid selected from together with the carbonatoms to which they are attached, can alanine, arginine, asparagine, aspartic acid, cysteine, form a cycloalkyl or Substituted cycloalkyl group; glutamic acid, glutamine, glycine, histidine, isoleucine, leu 0622 a is an integer from one to 8: cine, lysine, methionine, phenylalanine, proline, serine, 0623 provided that when a is one, the A ring is a hetero threonine, tryptophan, tyrosine, Valine, homoarginine, cyclic 6 to 12-membered ring; and when the A ring is a homolysine, ornithine, arginine mimic, arginine homologue, heterocyclic 5-membered ring, then a is an integer from 2 to arginine truncate, arginine with varying oxidation states, 8: lysine mimic, lysine homologue, lysine truncate, and lysine (0624) each R is independently hydrogen, alkyl, substi with varying oxidation states; tuted alkyl, aryl or substituted aryl; 0609) each R is a side chain of an amino acid indepen 0625 R represents a side chain of an amino acid, a side dently selected from alanine, arginine, asparagine, aspartic chain of an amino acid variant, a derivative of a side chain of acid, cysteine, glutamic acid, glutamine, glycine, histidine, an amino acid, or a derivative of a side chain of an amino acid isoleucine, leucine, lysine, methionine, phenylalanine, pro variant that effects –C(O)-CH(R) N(R)- to be a GI line, serine, threonine, tryptophan, tyrosine and valine; enzyme-cleavable moiety; 0610 b is a number from Zero to 100: (0626) each R represents a side chain of an amino acid 0611) R' is selected from hydrogen, alkyl, substituted independently selected from alanine, arginine, asparagine, alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted aspartic acid, cysteine, glutamic acid, glutamine, glycine, alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi histidine, isoleucine, leucine, lysine, methionine, phenylala tuted arylalkyl: nine, proline, serine, threonine, tryptophan, tyrosine and Valine; 0612 or a salt, hydrate or solvate thereof. 0627 b is a number from Zero to 100: 0613. The present embodiments provide a compound of (0628 R is selected from hydrogen, alkyl, substituted formula XIIIa: alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi tuted arylalkyl: (XIIIa) 0629 or a salt, hydrate or solvate thereof. O R R2 O R3 R6 0630. The present embodiments provide a compound of formula XIIIb:

X N A H R5 O RJ, (XIIIb) (Y), O R R2 O R3 R6

0614 wherein 0615. X represents a residue of an amide-containing active * Y-S agent, wherein —C(O) N(A ring)-Y. (CRR) A H R5 O RJ, NH C(O) CH(R) N(R) C(O) CH(R) N(R) (Y), R is connected to the amide-containing active agent through the oxygen of the amide group, wherein the amide 0631 wherein group is converted to an amide enol or an imine tautomer, 0632 X represents a residue of an amide-containing 0616 the A ring is a heterocyclic 5 to 12-membered ring: opioid, wherein - C(O) N(A ring)-Y. (CRR) 0617 each Y is independently selected from alkyl, substi NH CO) CH(R) N(R) C(O) CH(R) N(R) tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted R is connected to the amide-containing active agent alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car through the oxygen of the amide group, wherein the amide boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa group is converted to an amide enol or an imine tautomer, US 2014/O121 152 A1 May 1, 2014

0633 the A ring is a heterocyclic 5 to 12-membered ring: aliphatic amine group in an architecturally discrete way. See, 0634 each Y is independently selected from alkyl, substi for example, Foye's Principles of Medicinal Chemistry, Sixth tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted Edition, ed. T. L. Lemke and D. A. Williams, Lippincott alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car Williams & Wilkins, 2008, particularly Chapter 24, pages boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa 653-678. cyl. Substituted aminoacyl, amino, Substituted amino, acy lamino, Substituted acylamino, and cyano; 0649. For instance, the following opioids contain an amide 0635 c is a number from Zero to 3: group that can be a point of attachment to a promoiety: alfen 0636) each R" is independently selected from hydrogen, tanil, carfentanil, fentanyl, lofentanil, loperamide, olmefen alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, tanyl, remifentanil, and Sufentanil. substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, 0650. It is contemplated that opioids bearing at least some aminoacyl, Substituted aminoacyl, amino, Substituted amino, of the functionalities described herein will be developed; such acylamino, Substituted acylamino, and cyano; opioids are included as part of the scope of this disclosure. 0637 each R is independently selected from hydrogen, alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, Acetaminophen Prodrugs substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, 0651 “Acetaminophen' (i.e., para-acetylaminophenol, aminoacyl, Substituted aminoacyl, amino, Substituted amino, paracetamol, or APAP) refers to a chemical substance that acylamino, Substituted acylamino, and cyano; or exerts its pharmacological action by inhibiting cyclooxyge 0638) R' and R together with the carbon to which they are nase (COX), such as COX-2. Acetaminophen can be a syn attached can form a cycloalkyl or Substituted cycloalkyl thetic compound or a semi-synthetic compound. In certain group, or two R' or R groups on adjacent carbon atoms, embodiments, acetaminophen is a compound with a pharma together with the carbonatoms to which they are attached, can cophore that inhibits COX (e.g., COX-2) and has analgesic form a cycloalkyl or Substituted cycloalkyl group; and antipyretic effects. See, for example, Foye's Principles of 0639 a is an integer from one to 8: Medicinal Chemistry, Sixth Edition, ed. T. L. Lemke and D. 0640 provided that when a is one, the A ring is a hetero A. Williams, Lippincott Williams & Wilkins, 2008, particu cyclic 6 to 12-membered ring; and when the A ring is a larly Chapter 36, pages 959-965. heterocyclic 5-membered ring, thena is an integer from 2 to 8: 0652 The disclosure provides for an acetaminophen pro 0641 each R is independently hydrogen, alkyl, substi drug, wherein the acetaminophen has an optionally Substi tuted alkyl, aryl or substituted aryl; tuted acetaminophen structure: 0642 R represents a side chain of an amino acid, a side chain of an amino acid variant, a derivative of a side chain of an amino acid, or a derivative of a side chain of an amino acid variant that effects - C(O) CH(R) N(R) to be a GI enzyme-cleavable moiety; 0643 each R represents a side chain of an amino acid Or independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylala 0653. The disclosure provides an acetaminophen prodrug nine, proline, serine, threonine, tryptophan, tyrosine and that provides controlled release of acetaminophen. In an Valine; acetaminophen prodrug, a promoiety is attached to acetami 0644 b is a number from Zero to 100: (0645 R7 is selected from hydrogen, alkyl, substituted nophen through the phenolic oxygenatom wherein the hydro alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted genatom of the phenolic hydroxyl group of acetaminophen is alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi replaced by a covalent bond to the promoiety or through the tuted arylalkyl: oxygen of the amide group of acetaminophen, wherein the 0646 or a salt, hydrate or solvate thereof. amide group is converted to an amide enol or an imine tau 0647 Informula XI-XIII, X can be a residue of an amide tOmer. containing active agent, where the amide-containing active 0654. It is contemplated that acetaminophens bearing at agent is connected through the oxygen of the amide group, least some of the functionalities described herein will be wherein the amide group is converted to an amide enol or an developed; Such acetaminophens are included as part of the imine tautomer of an amide-containing opioid, where the Scope of this disclosure. amide-containing active agent is connected through the oxy gen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer. Formula XIV 0648. In certain embodiments, the amide-containing active agent is an amide-containing opioid. An "amide-con 0655 Compounds of the present disclosure include com taining opioid refers to a Subset of the opioids that contain an pounds of formula XIV shown below. Compositions of the amide group. As used herein, an amide-containing opioid is present disclosure also include compounds of formula XIV an opioid containing an enolizable amide group. An amide shown below. Pharmaceutical compositions and methods of containing opioid is a compound with a pharmacophore that the present disclosure also contemplate compounds of for presents to the opioid receptor an aromatic group and an mula XIV. US 2014/O121 152 A1 May 1, 2014 34

0656. The present embodiments provide a compound of stituted arylalkyl, heteroalkyl, substituted heteroalkyl, het formula XIV: eroaryl, substituted heteroaryl, heteroarylalkyl, and substi tuted heteroarylalkyl: 0670 b is a number from Zero to 100: 0671) R' is selected from hydrogen, alkyl, substituted alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi tuted arylalkyl: 0672 or a salt, hydrate or solvate thereof. 0673. In formula XIV. X represents acetaminophen, wherein the hydrogenatom of the phenolic hydroxyl group of acetaminophen is replaced by a covalent bond to —C(O)— N(A ring)-Y-(CRR). NH C(O)-CH(R) N (R) C(O) CH(R) N(R) R7: O wherein 0657 wherein —C(O) N(A ring)-Y-(CRR). NH-C(O)-CH 0658 X represents acetaminophen, wherein the hydrogen (R) N(R)-C(O)-CH(R) N(R) R7 is connected atom of the phenolic hydroxyl group of acetaminophen is to acetaminophen through the oxygen of the amide group of replaced by a covalent bond to —C(O)—N(A ring)-Y— acetaminophen, wherein the amide group is converted to an (CRR). NH CO) CH(R) N(R) C(O) CH amide enol or an imine tautomer. (R) N(R) R'; or wherein—C(O) N(A ring)-Y- 0674. In certain instances, X represents acetaminophen, (CRR). NH CO) CH(R) N(R) C(O) CH wherein the hydrogenatom of the phenolic hydroxyl group of (R) N(R) R' is connected to acetaminophen through acetaminophen is replaced by a covalent bond to —C(O)— the oxygen of the amide group of acetaminophen, wherein the N(A ring)-Y-(CRR). NH C(O)-CH(R) N amide group is converted to an amide enol or an imine tau (R) C(O) CH(R) N(R) R7. tomer, 0675. In certain instances, X represents acetaminophen, 0659 the A ring is a heterocyclic 5 to 12-membered ring: wherein –C(O) N(A ring)-Y-(CRR). NH C 0660 each Y is independently selected from alkyl, substi (O) CH(R) N(R) C(O) CH(R) N(R) R7 is tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted connected to acetaminophen through the oxygen of the amide alkynyl, aryl, substituted aryl, acyl, Substituted acyl, car group of acetaminophen, wherein the amide group is con boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa Verted to an amide enol or an imine tautomer. In certain cyl. Substituted aminoacyl, amino, Substituted amino, acy instances, X represents acetaminophen, wherein—C(O)—N lamino, Substituted acylamino, and cyano; (A ring)-Y-(CRR). NH C(O)-CH(R) N 0661 c is a number from Zero to 3: (R)-C(O)-CH(R) N(R) R' is connected to 0662 each R" is independently selected from hydrogen, acetaminophen through the oxygen of the amide group of alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, acetaminophen, wherein the amide group is converted to an substituted alkynyl, aryl, substituted aryl, acyl, substituted amide enol. In certain instances, X represents acetami acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, nophen, wherein - C(O) N(A ring)-Y. (CRR) aminoacyl, Substituted aminoacyl, amino, Substituted amino, NH CO) CH(R) N(R) C(O) CH(R) N(R) acylamino, Substituted acylamino, and cyano; R is connected to acetaminophen through the oxygen of 0663 each R is independently selected from hydrogen, the amide group of acetaminophen, wherein the amide group alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, is converted to an imine tautomer. substituted alkynyl, aryl, substituted aryl, acyl, substituted Compounds with Certain A Rings acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, Formulae XV-XVII aminoacyl, Substituted aminoacyl, amino, Substituted amino, acylamino, Substituted acylamino, and cyano; or 0676 Compounds of the present disclosure include com 0664) R' and R together with the carbon to which they are pounds of formulae XV-XVII shown below. Compositions of attached can form a cycloalkyl or Substituted cycloalkyl the present disclosure also include compounds of formulae group, or two R' or R groups on adjacent carbon atoms, XV-XVII shown below. Pharmaceutical compositions and together with the carbonatoms to which they are attached, can methods of the present disclosure also contemplate com form a cycloalkyl or Substituted cycloalkyl group; pounds of formulae XV-XVII. 0665 a is an integer from one to 8: 0677. The present embodiments provide a compound of 0666 provided that when a is one, the A ring is a hetero formula XVa: cyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8: (XVa) 0667 each R is independently hydrogen, alkyl, substi R R2 O R3 R6 tuted alkyl, aryl or substituted aryl; 0668 R is selected from hydrogen, alkyl, substituted Al N N alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, X l N11-A2 1- R7 heteroalkyl, substituted heteroalkyl, heteroaryl, substituted | A H R5 O RJ, heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl: A.NA41'N, A. 0669 each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, sub US 2014/O121 152 A1 May 1, 2014

0678 wherein 0693. The present embodiments provide a compound of 0679 X is selected from a residue of a ketone-containing formula XVb: active agent, wherein the hydrogenatom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to —C(O)—N(A ring)-Y— (XVb) (CRR). NH CO) CH(R) N(R) C(O) CH (R) N(R) R', a residue of a phenolic active agent, R R2 O R3 R6 wherein the hydrogenatom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—N(A ring)-Y— l Al a NN N N R7 X N11-A2 (CRR). NH C(O)-CH(R) N(R)-C(O)-CH | A H R5 O RJ, (R) N(R) R', and a residue of an amide-containing 5 3 active agent, wherein—C(O) N(A ring)-Y (CRR) N-N NH C(O) CH(R) N(R) C(O) CH(R) N(R) R is connected to the amide-containing opioid through the oxygen of the amide group, wherein the amide group is 0694 wherein converted to an amide enol or an imine tautomer, 0695 X is selected from a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding 0680 A', A, A, and Aare independently selected from hydroxyl group of the enolic tautomer of the ketone is carbon, nitrogen, oxygen, and Sulfur, replaced by a covalent bond to —C(O) NI (A ring)-Y— 0681 A is carbon or nitrogen; (CRR). NH CO) CH(R) N(R) C(O) CH 0682 each Y is independently selected from alkyl, substi (R) N(R) R': a residue of a phenolic opioid, wherein tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted the hydrogenatom of the phenolic hydroxyl group is replaced alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car by a covalent bond to C(O) N(A ring)-Y (CRR) boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa NH CO) CH(R) N(R) C(O) CH(R) N(R) cyl. Substituted aminoacyl, amino, Substituted amino, acy R', and a residue of an amide-containing opioid, wherein lamino, Substituted acylamino, and cyano; - C(O) N(A ring)-Y-(CRR). NH-C(O)-CH 0683 each R" is independently selected from hydrogen, (R) N(R)-C(O)-CH(R) N(R) R' is connected alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, to the amide-containing opioid through the oxygen of the substituted alkynyl, aryl, substituted aryl, acyl, substituted amide group, wherein the amide group is converted to an acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, amide enol or an imine tautomer, aminoacyl, Substituted aminoacyl, amino, Substituted amino, (0696 A, A, A, and Aare independently selected from acylamino, Substituted acylamino, and cyano; carbon, nitrogen, oxygen, and Sulfur, 0684 each R is independently selected from hydrogen, (0697 A is carbon or nitrogen; alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, 0698 each Y is independently selected from alkyl, substi substituted alkynyl, aryl, substituted aryl, acyl, substituted tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, alkynyl, aryl, Substituted aryl, acyl, Substituted acyl, car aminoacyl, Substituted aminoacyl, amino, Substituted amino, boxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoa acylamino, Substituted acylamino, and cyano; or cyl. Substituted aminoacyl, amino, Substituted amino, acy lamino, Substituted acylamino, and cyano; 0685) R' and R together with the carbon to which they are (0699 each R" is independently selected from hydrogen, attached can form a cycloalkyl or Substituted cycloalkyl alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, group, or two R' or R groups on adjacent carbon atoms, substituted alkynyl, aryl, substituted aryl, acyl, substituted together with the carbonatoms to which they are attached, can acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, form a cycloalkyl or Substituted cycloalkyl group; aminoacyl, Substituted aminoacyl, amino, Substituted amino, 0686) a is an integer from one to 8: acylamino, Substituted acylamino, and cyano; 0687 each R is independently hydrogen, alkyl, substi (0700 each R is independently selected from hydrogen, tuted alkyl, aryl or substituted aryl; alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, 0688 R is selected from hydrogen, alkyl, substituted substituted alkynyl, aryl, substituted aryl, acyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted aminoacyl, Substituted aminoacyl, amino, Substituted amino, heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl: acylamino, Substituted acylamino, and cyano; or 0689 each R is independently selected from hydrogen, (0701) R' and R together with the carbon to which they are alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, sub attached can form a cycloalkyl or Substituted cycloalkyl stituted arylalkyl, heteroalkyl, substituted heteroalkyl, het group, or two R' or R groups on adjacent carbon atoms, eroaryl, substituted heteroaryl, heteroarylalkyl, and substi together with the carbonatoms to which they are attached, can tuted heteroarylalkyl: form a cycloalkyl or Substituted cycloalkyl group; 0702 a is an integer from one to 8: 0690 b is a number from Zero to 100; and (0703) each R is independently hydrogen, alkyl, substi (0691) R' is selected from hydrogen, alkyl, substituted tuted alkyl, aryl or substituted aryl; alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted (0704) R is selected from hydrogen, alkyl, substituted alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, tuted arylalkyl: heteroalkyl, substituted heteroalkyl, heteroaryl, substituted 0692 or a salt, hydrate or solvate thereof. heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl: US 2014/O121 152 A1 May 1, 2014 36

(0705) each R is independently selected from hydrogen, together with the carbonatoms to which they are attached, can alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, sub form a cycloalkyl or Substituted cycloalkyl group; stituted arylalkyl, heteroalkyl, substituted heteroalkyl, het 0718 a is an integer from one to 8: eroaryl, substituted heteroaryl, heteroarylalkyl, and substi 0719 each R is independently hydrogen, alkyl, substi tuted heteroarylalkyl: tuted alkyl, aryl or substituted aryl; 0706 b is a number from Zero to 100; and 10720 R is a side chain of an amino acid selected from (0707 R’ is selected from hydrogen, alkyl, substituted alanine, arginine, asparagine, aspartic acid, cysteine, alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted glutamic acid, glutamine, glycine, histidine, isoleucine, leu alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi cine, lysine, methionine, phenylalanine, proline, serine, tuted arylalkyl: threonine, tryptophan, tyrosine, Valine, homoarginine, 0708 or a salt, hydrate or solvate thereof. homolysine, ornithine, arginine mimic, arginine homologue, 0709. The present embodiments provide a compound of arginine truncate, arginine with varying oxidation states, formula XVIa: lysine mimic, lysine homologue, lysine truncate, and lysine with varying oxidation states; 10721 each R is a side chain of an amino acid indepen (XVIa) dently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, R1 R2 O R3 R6 isoleucine, leucine, lysine, methionine, phenylalanine, pro line, serine, threonine, tryptophan, tyrosine and valine; l Al a NN N N R7 X N11-A2 0722 b is a number from Zero to 100: | A H R5 O RJ, 10723 R is selected from hydrogen, alkyl, substituted 5 3 alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted n -N alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi tuted arylalkyl: 0710 wherein 0724 or a salt, hydrate or solvate thereof. 0711 X is selected from a residue of a ketone-containing 0725. The present embodiments provide a compound of active agent, wherein the hydrogenatom of the corresponding formula XVIb: hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to —C(O)—N(A ring)-Y— (CRR). NH C(O)-CH(R) N(R)-C(O)-CH (XVIb) (R) N(R) R', a residue of a phenolic active agent, R R2 wherein the hydrogenatom of the phenolic hydroxyl group is O O R3 R6 replaced by a covalent bond to —C(O)—N(A ring)-Y— 7 (CRR). NH CO) CH(R) N(R) C(O) CH ls A. N R (R) N(R) R', and a residue of an amide-containing X N1-A2 N N active agent, wherein—C(O) N (A ring)-Y (CRR), l A k l R5 O k NH C(O) CH(R) N(R) C(O) CH(R) N(R) NA41'N, R is connected to the amide-containing opioid through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer, 0726 wherein 0712 A', A, A, and Aare independently selected from 0727 X is selected from a residue of a ketone-containing carbon, nitrogen, oxygen, and Sulfur, opioid, wherein the hydrogen atom of the corresponding 0713) A is carbon or nitrogen; hydroxyl group of the enolic tautomer of the ketone is 0714 Y is selected from alkyl, substituted alkyl, alkenyl, replaced by a covalent bond to —C(O) NI (A ring)-Y— Substituted alkenyl, alkynyl. Substituted alkynyl, aryl, Substi (CRR). NH C(O)-CH(R) N(R)-C(O)-CH tuted aryl, acyl, Substituted acyl, carboxyl, alkoxycarbonyl, (R) N(R) R', a residue of a phenolic opioid, wherein Substituted alkoxycarbonyl, aminoacyl, Substituted aminoa the hydrogenatom of the phenolic hydroxyl group is replaced cyl, amino, Substituted amino, acylamino, Substituted acy by a covalent bond to C(O) N (A ring)-Y—(CRR), lamino, and cyano; NH CO) CH(R) N(R) C(O) CH(R) N(R) 0715 each R" is independently selected from hydrogen, R', and a residue of an amide-containing opioid, wherein alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, —C(O) N(A ring)-Y-(CRR). NH-C(O)-CH substituted alkynyl, aryl, substituted aryl, acyl, substituted (R) N(R)-C(O)-CH(R) N(R) R7 is connected acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, to the amide-containing opioid through the oxygen of the aminoacyl, Substituted aminoacyl, amino, Substituted amino, amide group, wherein the amide group is converted to an acylamino, Substituted acylamino, and cyano; amide enol or an imine tautomer, 0716) each R is independently selected from hydrogen, 0728 A, A, A, and Aare independently selected from alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, carbon, nitrogen, oxygen, and Sulfur, substituted alkynyl, aryl, substituted aryl, acyl, substituted 0729) A is carbon or nitrogen: acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, 0730 Y is selected from alkyl, substituted alkyl, alkenyl, aminoacyl, Substituted aminoacyl, amino, Substituted amino, Substituted alkenyl, alkynyl. Substituted alkynyl, aryl, Substi acylamino, Substituted acylamino, and cyano; or tuted aryl, acyl, Substituted acyl, carboxyl, alkoxycarbonyl, 0717 R and R together with the carbon to which they are Substituted alkoxycarbonyl, aminoacyl, Substituted aminoa attached can form a cycloalkyl or Substituted cycloalkyl cyl, amino, Substituted amino, acylamino, Substituted acy group, or two R' or R groups on adjacent carbon atoms, lamino, and cyano; US 2014/O121 152 A1 May 1, 2014 37

(0731 each R" is independently selected from hydrogen, active agent, wherein—C(O) N (A ring)-Y (CRR), alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, NH CO) CH(R) N(R) C(O) CH(R) N(R) substituted alkynyl, aryl, substituted aryl, acyl, substituted R is connected to the amide-containing opioid through acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, the oxygen of the amide group, wherein the amide group is aminoacyl, Substituted aminoacyl, amino, Substituted amino, converted to an amide enol or an imine tautomer, acylamino, Substituted acylamino, and cyano; 10744) A', A, A, and Aare independently selected from (0732 each R is independently selected from hydrogen, carbon, nitrogen, oxygen, and Sulfur, alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, 0745) A is carbon or nitrogen; substituted alkynyl, aryl, substituted aryl, acyl, substituted 0746 Y is selected from alkyl, substituted alkyl, alkenyl, acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, Substituted alkenyl, alkynyl. Substituted alkynyl, aryl, Substi aminoacyl, Substituted aminoacyl, amino, Substituted amino, tuted aryl, acyl, Substituted acyl, carboxyl, alkoxycarbonyl, acylamino, Substituted acylamino, and cyano; or Substituted alkoxycarbonyl, aminoacyl, Substituted aminoa (0733 R' and R together with the carbon to which they are cyl, amino, Substituted amino, acylamino, Substituted acy attached can form a cycloalkyl or Substituted cycloalkyl lamino, and cyano; group, or two R' or R groups on adjacent carbon atoms, 0747 each R" is independently selected from hydrogen, together with the carbonatoms to which they are attached, can alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, form a cycloalkyl or Substituted cycloalkyl group; substituted alkynyl, aryl, substituted aryl, acyl, substituted 0734 a is an integer from one to 8: acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, (0735) each R is independently hydrogen, alkyl, substi aminoacyl, Substituted aminoacyl, amino, Substituted amino, tuted alkyl, aryl or substituted aryl; acylamino, Substituted acylamino, and cyano; (0736 R is a side chain of an amino acid selected from 10748 each R is independently selected from hydrogen, alanine, arginine, asparagine, aspartic acid, cysteine, alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, glutamic acid, glutamine, glycine, histidine, isoleucine, leu substituted alkynyl, aryl, substituted aryl, acyl, substituted cine, lysine, methionine, phenylalanine, proline, serine, acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, threonine, tryptophan, tyrosine, Valine, homoarginine, aminoacyl, Substituted aminoacyl, amino, Substituted amino, homolysine, ornithine, arginine mimic, arginine homologue, acylamino, Substituted acylamino, and cyano; or arginine truncate, arginine with varying oxidation states, 0749 RandR together with the carbon to which they are lysine mimic, lysine homologue, lysine truncate, and lysine attached can form a cycloalkyl or Substituted cycloalkyl with varying oxidation states; group, or two R' or R groups on adjacent carbon atoms, 0737 each R is a side chain of an amino acid indepen together with the carbonatoms to which they are attached, can dently selected from alanine, arginine, asparagine, aspartic form a cycloalkyl or Substituted cycloalkyl group; acid, cysteine, glutamic acid, glutamine, glycine, histidine, 0750 a is an integer from one to 8: isoleucine, leucine, lysine, methionine, phenylalanine, pro (0751 each R is independently hydrogen, alkyl, substi line, serine, threonine, tryptophan, tyrosine and valine; tuted alkyl, aryl or substituted aryl; 0738 b is a number from Zero to 100: (0752 R represents a side chain of an amino acid, a side (0739) R' is selected from hydrogen, alkyl, substituted chain of an amino acid variant, a derivative of a side chain of alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted an amino acid, or a derivative of a side chain of an amino acid alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi variant that effects - C(O)-CH(R) N(R) to be a GI tuted arylalkyl: enzyme-cleavable moiety; 0740 or a salt, hydrate or solvate thereof. (0753 each R represents a side chain of an amino acid 0741. The present embodiments provide a compound of independently selected from alanine, arginine, asparagine, formula XVIIa: aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylala nine, proline, serine, threonine, tryptophan, tyrosine and (XVIIa) Valine; 0754 b is a number from Zero to 100: 2 O R. R. O R3 R6 (0755) R' is selected from hydrogen, alkyl, substituted alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi X ls N1-A2 *s N N N R7 tuted arylalkyl: l A k l R5 O 0756 or a salt, hydrate or solvate thereof. NA41'N, 0757. The present embodiments provide a compound of formula XVII: 0742 wherein 0743 X is selected from a residue of a ketone-containing (XVII) active agent, wherein the hydrogenatom of the corresponding hydroxyl group of the enolic tautomer of the ketone is 2 replaced by a covalent bond to —C(O)—N(A ring)-Y— (CRR). NH CO) CH(R) N(R) C(O) CH O -4 O NR3 R6 R7 (R) N(R) R': a residue of a phenolic active agent, X ls, -y NA2 N wherein the hydrogenatom of the phenolic hydroxyl group is l A k h R5 O k replaced by a covalent bond to —C(O)—N(A ring)-Y— NA41'N, (CRR). NH CO) CH(R) N(R) C(O) CH (R) N(R) R', and a residue of an amide-containing US 2014/O121 152 A1 May 1, 2014

0758 wherein the hydrogen atom of the corresponding hydroxyl group of 0759 X is selected from a residue of a ketone-containing the enolic tautomer of the ketone is replaced by a covalent opioid, wherein the hydrogen atom of the corresponding bond to –C(O) N (A ring)-Y-(CRR). NH C hydroxyl group of the enolic tautomer of the ketone is (O)-CH(R) N(R)-C(O)-CH(R) N(R) R7; a replaced by a covalent bond to —C(O)—N(A ring)-Y— residue of a phenolic active agent or opioid, wherein the (CRR). NH C(O)-CH(R) N(R)-C(O)-CH hydrogenatom of the phenolic hydroxyl group is replaced by (R) N(R) R', a residue of a phenolic opioid, wherein a covalent bond to C(O) N (A ring)-Y-(CRR), the hydrogenatom of the phenolic hydroxyl group is replaced NH CO) CH(R) N(R) C(O) CH(R) N(R) by a covalent bond to C(O) N(A ring)-Y (CRR) R', and a residue of an amide-containing active agent or NH C(O) CH(R) N(R) C(O) CH(R) N(R) opioid, wherein –C(O) NI (A ring)-Y-(CRR), R'; and a residue of an amide-containing opioid, wherein NH CO) CH(R) N(R) C(O) CH(R) N(R) —C(O) N(A ring)-Y-(CRR). NH C(O)-CH R is connected to the amide-containing opioid through (R) N(R)-C(O)-CH(R) N(R) R7 is connected the oxygen of the amide group, wherein the amide group is to the amide-containing opioid through the oxygen of the converted to an amide enol or an imine tautomer. amide group, wherein the amide group is converted to an 0774. In certain instances, X is a ketone-containing amide enol or an imine tautomer, opioid, wherein the hydrogen atom of the corresponding 0760 A, A, A, and Aare independently selected from hydroxyl group of the enolic tautomer of the ketone is carbon, nitrogen, oxygen, and Sulfur, replaced by a covalent bond to —C(O) NI (A ring)-Y— 0761) A is carbon or nitrogen; (CRR). NH CO) CH(R) N(R) C(O) CH 0762 Y is selected from alkyl, substituted alkyl, alkenyl, (R) N(R) R7. Substituted alkenyl, alkynyl. Substituted alkynyl, aryl, Substi 0775. In certain instances, X is a ketone-containing tuted aryl, acyl, Substituted acyl, carboxyl, alkoxycarbonyl, opioid, wherein the opioid is selected from acetylmorphone, Substituted alkoxycarbonyl, aminoacyl, Substituted aminoa hydrocodone, hydromorphone, ketobemidone, methadone, cyl, amino, Substituted amino, acylamino, Substituted acy naloxone, naltrexone, N-methylnaloxone, N-methylmaltrex lamino, and cyano; one, oxycodone, oxymorphone, and pentamorphone. 0763 each R" is independently selected from hydrogen, 0776. In certain instances, X is a residue of a phenolic alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, opioid, wherein the hydrogen atom of the phenolic hydroxyl substituted alkynyl, aryl, substituted aryl, acyl, substituted group is replaced by a covalent bond to —C(O)—N (A ring)- acyl, carboxyl, alkoxycarbonyl. Substituted alkoxycarbonyl, Y-(CRR). NH C(O)-CH(R) N(R)-C(O) aminoacyl, Substituted aminoacyl, amino, Substituted amino, CH(R) N(R) R7. acylamino, Substituted acylamino, and cyano; 0777. In certain instances, X is a phenolic opioid, wherein 0764 each R is independently selected from hydrogen, the opioid is selected from buprenorphine, dihydroetorphine, alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, diprenorphine, etorphine, hydromorphone, levorphanol, substituted alkynyl, aryl, substituted aryl, acyl, substituted morphine, nalbuphine, nalmefene, nalorphine, naloxone, nal acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, trexone, N-methyldiprenorphine, N-methylnaloxone, N-me aminoacyl, Substituted aminoacyl, amino, Substituted amino, thylmaltrexone, oripavine, oxymorphone, butorphanol, dezo acylamino, Substituted acylamino, and cyano; or cine, ketobemidone, meptazinol, o-desmethyltramadol, 0765 RandR together with the carbon to which they are pentazocine, phenazocine, and tapentadol. attached can form a cycloalkyl or Substituted cycloalkyl 0778. In certain instances, X is a residue of an amide group, or two R' or R groups on adjacent carbon atoms, containing opioid, wherein —C(O)—N(A ring)-Y— together with the carbonatoms to which they are attached, can (CRR). NH CO) CH(R) N(R) C(O) CH form a cycloalkyl or Substituted cycloalkyl group; (R) N(R) R' is connected to the amide-containing 0766 a is an integer from one to 8: opioid through the oxygen of the amide group, wherein the 0767 each R is independently hydrogen, alkyl, substi amide group is converted to an amide enol or an imine tau tuted alkyl, aryl or substituted aryl; tOmer. 0768 R represents a side chain of an amino acid, a side 0779. In certain instances, X is an amide-containing chain of an amino acid variant, a derivative of a side chain of opioid, wherein the opioid is selected from alfentanil, carfen an amino acid, or a derivative of a side chain of an amino acid tanil, fentanyl, lofentanil, loperamide, olmefentanyl. variant that effects –C(O)-CH(R) N(R)- to be a GI remifentanil, and Sufentanil. enzyme-cleavable moiety; 0780. In formulae XV-XVII, A", A, A, and Aare inde 0769 each R represents a side chain of an amino acid pendently selected from carbon, nitrogen, oxygen, and Sulfur. independently selected from alanine, arginine, asparagine, In certain instances, A', A, A, and A are independently aspartic acid, cysteine, glutamic acid, glutamine, glycine, selected from carbon and nitrogen. In certain instances, A', histidine, isoleucine, leucine, lysine, methionine, phenylala A, A, and A are independently selected from carbon and nine, proline, serine, threonine, tryptophan, tyrosine and oxygen. In certain instances, A', A, A, and Aare indepen Valine; dently selected from carbon and Sulfur. In certain instances, (0770 b is a number from Zero to 100: A'. A. A. and Aare carbon. 0771) R' is selected from hydrogen, alkyl, substituted 0781. In formulae XV-XVII, A is carbon or nitrogen. In alkyl, acyl, Substituted acyl, alkoxycarbonyl. Substituted certain instances, A is carbon. In certain instances, A is alkoxycarbonyl, aryl, Substituted aryl, arylalkyl, and Substi nitrogen. tuted arylalkyl: 0782. In certain instances, -(CRR). NH-C(O)— 0772 or a salt, hydrate or solvate thereof. CH(R) N(R) C(O) CH(R) N(R) R7 is (0773. In formulae XV-XVII, X can be selected from a attached to A'. In certain instances, —(CRR). NH C residue of a ketone-containing active agent or opioid, wherein (O) CH(R) N(R) C(O) CH(R) N(R) R7 is US 2014/O121 152 A1 May 1, 2014 39 attached to A. In certain instances, —(CRR), NH C amino. In certain instances, Y is acylamino or Substituted (O) CH(R) N(R) C(O) CH(R) N(R) R7 is acylamino. In certain instances, Y is acylamino. In certain attached to A. In certain instances, —(CRR), NH C (O) CH(R) N(R)-C(O)-CH(R) N(R) R7 is instances, Y is Substituted acylamino. In certain instances, Y attached to A. is cyano. 0791. In certain instances, Y is substituted alkyl. In certain Certain Embodiments of Formulae I-XVII instances, Y is an alkyl group Substituted with a carboxylic 0783 Informulae I-XIV, the A ring can be a heterocyclic group Such as a carboxylic acid, alkoxycarbonyl or aminoa 5 to 12-membered ring. cyl. In certain instances, Y is -(CH2)(CH4)-COOH, 0784. In certain instances, the A ring is a heterocyclic 5 to -(CH2)(C.H.) COOCH, O -(CH2)(CH)— 11-membered ring. In certain instances, the A ring is a het COOCHCH, where q is an integer from one to 10. In certain erocyclic 5 to 10-membered ring. In certain instances, the A instances, Y is aminoacyl. In certain instances, Y is an alkyl ring is a heterocyclic 5 to 9-membered ring. In certain group Substituted with an amino group, Substituted amino, or instances, the A ring is a heterocyclic 5 to 8-membered ring. acylamino. In certain instances, the A ring is a heterocyclic 5 to 7-mem bered ring. In certain instances, the A ring is a heterocyclic 5 0792. In certain instances, Y is aminoacyl or substituted or 6-membered ring. In certain instances, the A ring is a aminoacyl. heterocyclic 5-membered ring. 0793. In certain instances, Y is aminoacyl comprising phe 0785. In certain instances, the A ring is a heterocyclic 6 to nylenediamine. In certain instances, Y is 12-membered ring. In certain instances, the A ring is a het erocyclic 6 to 11-membered ring. In certain instances, the A ring is a heterocyclic 6 to 10-membered ring. In certain instances, the A ring is a heterocyclic 6 to 9-membered ring. In certain instances, the A ring is a heterocyclic 6 to 8-mem bered ring. In certain instances, the A ring is a heterocyclic 6 or 7-membered ring. In certain instances, the A ring is a heterocyclic 6-membered ring. In certain instances, the A ring is a heterocyclic 7-membered ring. In certain instances, the A ring is a heterocyclic 8-membered ring. wherein each R' is independently selected from hydrogen, 0786 Informulae I-XVII, c can be a number from Zero to alkyl, substituted alkyl, and acyl and R'' is alkyl or substi 3. In certain instances, c is Zero. In certain instances, c is 1. In tuted alkyl. In certain instances, at least one of R' is acyl. In certain instances, c is 2. In certain instances, c is 3. certain instances, at least one of R' is alkyl or substituted 0787. In formulae I-XVII, each Y is independently alkyl. In certain instances, at least one of R" is hydrogen. In selected from alkyl, substituted alkyl, alkenyl, substituted certain instances, both of R'' are hydrogen. alkenyl, alkynyl. Substituted alkynyl, aryl, Substituted aryl, 0794. In certain instances, Y is acyl, Substituted acyl, carboxyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aminoacyl, Substituted aminoacyl, amino, Substituted amino, acylamino, Substituted acylamino, and cyano. 0788. In formulae I-XVII, Y can be carboxyl or amino. In certain instances, Y is carboxyl. In certain instances, Y is amino. 0789. In certain instances. Y is alkyl or substituted alkyl. In certain instances, Y is alkyl. In certain instances, Y is Substi tuted alkyl. In certain instances, Y is alkenyl or substituted alkenyl. In certain instances. Y is alkenyl. In certain instances, wherein R' is hydrogen, alkyl, substituted alkyl, or acyl. In Y is substituted alkenyl. In certain instances, Y is alkynyl or certain instances, R' is acyl. In certain instances, R' is alkyl Substituted alkynyl. In certain instances, Y is alkynyl. In cer or substituted alkyl. In certain instances, R' is hydrogen. tain instances, Y is Substituted alkynyl. In certain instances, Y is aryl or Substituted aryl. In certain instances, Y is aryl. In 0795. In certain instances, Y is certain instances, Y is substituted aryl. 0790. In certain instances, Y is acyl or substituted acyl. In certain instances, Y is acyl. In certain instances, Y is Substi tuted acyl. In certain instances, Y is carboxyl. In certain instances, Y is alkoxycarbonyl or Substituted alkoxycarbonyl. In certain instances. Y is alkoxycarbonyl. In certain instances, Y is substituted alkoxycarbonyl. In certain instances, Y is aminoacyl or Substituted aminoacyl. In certain instances. Y is aminoacyl. In certain instances. Y is Substituted aminoacyl. In wherein each R' is independently hydrogen, alkyl, substi certain instances, Y is amino or Substituted amino. In certain tuted alkyl, or acyl and b is a number from one to 5. In certain instances, Y is amino. In certain instances, Y is Substituted instances, Y is US 2014/O121 152 A1 May 1, 2014 40

instances, a is 5. In certain instances, a is 6. In certain R10 instances, a is 7. In certain instances, a is 8. (0804) In formulae I-XVII, each R" is independently N selected from hydrogen, alkyl, Substituted alkyl, alkenyl, Sub s YR 10. stituted alkenyl, alkynyl. Substituted alkynyl, aryl, Substituted O aryl, acyl, Substituted acyl, carboxyl, alkoxycarbonyl, Substi tuted alkoxycarbonyl, aminoacyl, Substituted aminoacyl, wherein each R' is independently hydrogen, alkyl, substi amino, Substituted amino, acylamino, Substituted acylamino, tuted alkyl, or acyl. In certain instances, Y is and cyano. (0805. In certain instances, R is hydrogen. In certain instances, R' is alkylor substituted alkyl. In certain instances, R" is alkyl. In certain instances, R is substituted alkyl. In certain instances, R' is alkenyl or substituted alkenyl. In cer tain instances, R' is alkenyl. In certain instances, R' is sub stituted alkenyl. In certain instances, R' is alkynyl or substi R10a O tuted alkynyl. In certain instances, R' is alkynyl. In certain instances, R' is substituted alkynyl. In certain instances, R' is aryl or substituted aryl. In certain instances, R' is aryl. In wherein R' is alkyl and each R' is independently hydro certain instances, R' is substituted aryl. In certain instances, gen, alkyl, Substituted alkyl, or acyl. R" is acyl or substituted acyl. In certain instances, R' is acyl. 0796. In certain instances, Y is In certain instances, R' is substituted acyl. In certain instances, R' is carboxyl. In certain instances, R' is alkoxy carbonyl or Substituted alkoxycarbonyl. In certain instances, O R" is alkoxycarbonyl. In certain instances, R' is substituted OH: alkoxycarbonyl. In certain instances, R' is aminoacyl or sub N stituted aminoacyl. In certain instances, R' is aminoacyl. In R10 O certain instances, R' is substituted aminoacyl. In certain instances, R' is amino or substituted amino. In certain instances, R' is amino. In certain instances, R' is substituted wherein R' is independently hydrogen, alkyl, substituted amino. In certain instances, R' is acylamino or substituted alkyl, or acyl and b is a number from one to 5. In certain acylamino. In certain instances, R' is acylamino. In certain instances, Y is instances, R' is substituted acylamino. In certain instances, R" is cyano. O (0806. In formulae I-XVII, each R is independently selected from hydrogen, alkyl, Substituted alkyl, alkenyl, Sub OH: stituted alkenyl, alkynyl. Substituted alkynyl, aryl, Substituted N aryl, acyl, Substituted acyl, carboxyl, alkoxycarbonyl, Substi R10 O tuted alkoxycarbonyl, aminoacyl, Substituted aminoacyl, amino, Substituted amino, acylamino, Substituted acylamino, and cyano. wherein R' is independently hydrogen, alkyl, substituted (0807. In certain instances, R is hydrogen. In certain alkyl, or acyl. instances, R is alkylor Substituted alkyl. In certain instances, 0797. In certain instances, Y is an aminoacyl group, such R’ is alkyl. In certain instances, R is substituted alkyl. In as C(O)NR'R'', wherein each R'' and R' is inde certain instances, R is alkenyl or substituted alkenyl. In cer pendently selected from hydrogen, alkyl, Substituted alkyl, tain instances, R is alkenyl. In certain instances, R is sub and acyl. In certain instances, Y is an aminoacyl group. Such stituted alkenyl. In certain instances, R is alkynyl or substi as C(O)NR'R'', wherein R' is an alkyl and R' is tuted alkynyl. In certain instances, R is alkynyl. In certain Substituted alkyl. In certain instances, Y is an aminoacyl instances, R is substituted alkynyl. In certain instances, R is group, such as –C(O)NR'R'', wherein R' is an alkyl aryl or substituted aryl. In certain instances, R is aryl. In and R' is alkyl substituted with a carboxylic acid oralkoxy certain instances, R is substituted aryl. In certain instances, carbonyl. In certain instances, Y is an aminoacyl group. Such R’ is acyl or substituted acyl. In certain instances, R is acyl. as C(O)NR'R'' wherein R' is methyland R' is alkyl In certain instances, R is substituted acyl. In certain substituted with a carboxylic acid or alkoxycarbonyl. instances, R is carboxyl. In certain instances, R is alkoxy 0798. In certain instances, Y is carboxyl. carbonyl or Substituted alkoxycarbonyl. In certain instances, 0799. In certain instances, Y is acyl or substituted acyl. R’ is alkoxycarbonyl. In certain instances, R is substituted 0800. In certain instances, Y is alkoxycarbonyl or substi alkoxycarbonyl. In certain instances, R is aminoacyl or Sub tuted alkoxycarbonyl. stituted aminoacyl. In certain instances, R is aminoacyl. In 0801. In certain instances, Y is amino or substituted certain instances, R is substituted aminoacyl. In certain amino. instances, R is amino or substituted amino. In certain 0802. In certain instances, Y is acylamino or substituted instances, R is amino. In certain instances, R is substituted acylamino. amino. In certain instances, R is acylamino or substituted 0803 Informulae I-XVII, a can be an integer from one to acylamino. In certain instances, R is acylamino. In certain 8. In certain instances, a is one. In certain instances, a is 2. In instances, R is substituted acylamino. In certain instances, certain instances, a is 3. In certain instances, a is 4. In certain R’ is cyano. US 2014/O121 152 A1 May 1, 2014

(0808. In certain instances, one of RandR is hydrogen. In certain instances, one of R' and R is alkyl. In certain instances, one of R' and R is substituted alkyl. In certain instances, one of R' and R is alkenyl or substituted alkenyl. In certain instances, one of RandR is alkynylor substituted alkynyl. In certain instances, one of R' and R is aryl or substituted aryl. In certain instances, one of R' and R is acyl or substituted acyl. In certain instances, one of R' and R is wherein each R' is independently selected from hydrogen, carboxyl. In certain instances, one of R' and R is alkoxycar alkyl, substituted alkyl, and acyl and R'' is alkyl or substi bonyl or Substituted alkoxycarbonyl. In certain instances, one tuted alkyl. In certain instances, at least one of R" is acyl. In of RandR is aminoacylor substitutedaminoacyl. In certain certain instances, at least one of R' is alkyl or substituted instances, one of R' and R is amino or substituted amino. In alkyl. In certain instances, at least one of R" is hydrogen. In certain instances, one of RandR is acylamino or substituted certain instances, both of R'' are hydrogen. acylamino. In certain instances, one of R' and R is cyano. (0816) In certain instances, one of R' and R is (0809. In certain instances, R' and R are hydrogen. In certain instances, R' and R on the same carbon are both alkyl. In certain instances, R' and R on the same carbon are methyl. In certain instances, RandR on the same carbon are ethyl. 0810. In certain instances, R' and R' which are vicinal are both alkyland RandR which are vicinal are both hydrogen. In certain instances, RandR' which are vicinal are both ethyl and RandR which are vicinal are both hydrogen. In certain wherein R' is hydrogen, alkyl, substituted alkyl, or acyl. In instances, RandR' which are vicinal are both methylandR certain instances, R' is acyl. In certain instances, R' is alkyl and R which are vicinal are both hydrogen. or substituted alkyl. In certain instances, R' is hydrogen. 0811. In certain instances, in the chain of —C(R')(R) 0817. In certain instances, one of R' and R is , not every carbon is substituted. In certain instances, in the chain of —C(R')(R). , there is a combination of different alkyl substituents, such as methyl or ethyl. O R10 0812. In certain instances, one or both of R' and R is N substituted alkyl. In certain instances, one or both of R' and x's NR 10, R is an alkyl group Substituted with a carboxylic group such R10 O as a carboxylic acid, alkoxycarbonyl or aminoacyl. In certain instances, one or both of R' and R is -(CH2)(CH)— COOH, -(CH2)(CH) COOCH, or -(CH2)(CH)— wherein each R' is independently hydrogen, alkyl, substi COOCHCH, where q is an integer from one to 10. In certain tuted alkyl, or acyl and b is a number from one to 5. In certain instances, one or both of R and R is aminoacyl. instances, one of R' and R is 0813. In formulae I-XVII, R' and R together with the carbon to which they are attached can form a cycloalkyl or Substituted cycloalkyl group, or two R' or R groups on adja O R10 cent carbon atoms, together with the carbon atoms to which N they are attached, can form a cycloalkyl or Substituted cycloalkyl group. In certain instances, R' and R together R10 O with the carbon to which they are attached can form a cycloalkyl group. Thus, in certain instances, RandR on the same carbon form a spirocycle. In certain instances, RandR wherein each R" is independently hydrogen, alkyl, substi together with the carbon to which they are attached can form tuted alkyl, or acyl. In certain instances, one of R' and R is a substituted cycloalkyl group. In certain instances, two R' or R groups on adjacent carbonatoms, together with the carbon atoms to which they are attached, can form a cycloalkyl O R10 group. In certain instances, two R' or R groups on adjacent carbon atoms, together with the carbon atoms to which they N are attached, can form a Substituted cycloalkyl group. 0814 In certain instances, one of R' and R is aminoacyl. R10a O 0815) In certain instances, one of R' and R is aminoacyl comprising phenylenediamine. In certain instances, one or wherein R' is alkyl and each R' is independently hydro both of R' and R is gen, alkyl, Substituted alkyl, or acyl. US 2014/O121 152 A1 May 1, 2014 42

0818. In certain instances, one of R' and R is an oxo (=O) Substituent, a nitrile group, a nitro group, ether groups (for example an alkoxy group) and phenyl groups bearing a Substituent at the orthoposition, the paraposition or O both the ortho and the para positions, each substituent being selected independently from a halogen atom, a fluoroalkyl OH: N group (such as trifluoromethyl), a nitro group, a cyano group and a carboxyl group. Each of the electron withdrawing Sub R10 O stituents can be selected independently from these. (0827. In certain instances. -IC(R')(R) is selected wherein R' is independently hydrogen, alkyl, substituted from -CH(CHF)CH(CHF) : -CH(CHF)CH alkyl, or acyl and b is a number from one to 5. In certain (CHF) : —CH(CF)CH(CF)–: —CHCH(CF) : instances, one of R' and R is —CHCH(CHF)–: —CHCH(CHF) : —CHCH(F) CH. : CHC(F)CH. : CHCH(C(O)NR'OR') : CHCH(C(O)CR) : CH-CH(C(O)CH) : CH O (CHF)CHCH(CHF) : CH(CHF)CHCH(CHF) : OH: —CH(CF)CH-CH(CF) : - CHCH-CH(CF) : N —CHCH-CH(CHF)–: —CHCH-CH(CHF) : CHCH-CH(C(O)NR'R') : CHCH-CH(C(O) R10 O OR) ; and CHCH-CH(C(O)OH) , in which R', R', R’ and Reach independently represents hydrogen or wherein R' is independently hydrogen, alkyl, substituted (1-6C)alkyl, and Rand Reach independently represents alkyl, or acyl. (1-6C)alkyl. 0819. In certain instances, one of R' and R is an aminoa 0828. In formulae I-XIV, when a is one, the A ring is a cyl group, such as –C(O)NR'R'', wherein each R'' and heterocyclic 6 to 12-membered ring; and when the A ring is a R" is independently selected from hydrogen, alkyl, substi heterocyclic 5-membered ring, then a is an integer from 2 to tuted alkyl, and acyl. In certain instances, one of R' and R is an aminoacyl group, such as C(O)NR'R'', wherein 8. R" is an alkyl and R' is substituted alkyl. In certain 0829. In certain instances, when a is one, the A ring is a instances, one of R' and R is an aminoacyl group, such as heterocyclic 6 to 11-membered ring. In certain instances, C(O)NR'R'', wherein R' is an alkyl and R' is alkyl when a is one, the A ring is a heterocyclic 6 to 10-membered substituted with a carboxylic acid or alkoxycarbonyl. In cer ring. In certain instances, when a is one, the A ring is a tain instances, one of R' and R is an aminoacyl group, such heterocyclic 6 to 9-membered ring. In certain instances, when as C(O)NR'R'', wherein R is methyl and R is a is one, the A ring is a heterocyclic 6 to 8-membered ring. In alkyl substituted with a carboxylic acid or alkoxycarbonyl. certain instances, whena is one, the A ring is a heterocyclic 6 0820. In certain instances, one of R' and Rare carboxyl. to 7-membered ring. In certain instances, whena is one, the A 0821. In certain instances, one of R' and R is acyl or ring is a heterocyclic 6-membered ring. substituted acyl. 0830. In certain instances, when the A ring is a heterocy 0822. In certain instances, one of R' and R is alkoxycar clic 5-membered ring, then a is an integer from 2 to 7. In bonyl or substituted alkoxycarbonyl. certain instances, when the A ring is a heterocyclic 5-mem 0823. In certain instances, one of R' and R is amino or bered ring, then a is an integer from 2 to 6. In certain Substituted amino. instances, when the A ring is a heterocyclic 5-membered ring, 0824. In certain instances, one of R' and R is acylamino thena is an integer from 2 to 5. In certain instances, when the or Substituted acylamino. A ring is a heterocyclic 5-membered ring, thena is an integer 0825. In certain instances, R' or R can modulate a rate of from 2 to 4. In certain instances, when the A ring is a hetero intramolecular cyclization. R' or R can speed up a rate of cyclic 5-membered ring, then a is an integer from 2 to 3. In intramolecular cyclization, when compared to the corre certain instances, when the A ring is a heterocyclic 5-mem sponding molecule where R' and R are both hydrogen. In bered ring, then a is 2. certain instances, R' or R comprise an electron-withdrawing 0831. In certain instances, the A ring is a heterocyclic group or an electron-donating group. In certain instances, R' 7-membered or 8-membered ring and a is 1 or 2. In certain or R comprise an electron-withdrawing group. In certain instances, the A ring is a heterocyclic 7-membered ring and a instances, R' or R comprise an electron-donating group. is 1. In certain instances, the A ring is a heterocyclic 7-mem 0826 Atoms and groups capable of functioning as elec bered ring and a is 2. In certain instances, the A ring is a tron-withdrawing substituents are well known in the field of heterocyclic 8-membered ring and a is 1. In certain instances, organic chemistry. They include electronegative atoms and the A ring is a heterocyclic 8-membered ring and a is 2. groups containing electronegative atoms. Such groups func 0832. In certain instances, a certain group of compounds tion to lower the basicity or protonation state of a nucleophilic are compounds of formulae I-XIV, wherein A ring is a nitrogen in the beta position via inductive withdrawal of 5-membered ring anda is 2. A certain group of compounds are electron density. Such groups can also be positioned on other compounds of formulae I-XIV, wherein A ring is a 6-mem positions along the alkylene chain. Examples include halogen bered ring and a is one. atoms (for example, a fluorine atom), acyl groups (for example an alkanoyl group, anaroyl group, a carboxyl group, 0833. In formulae I-XVII, each R can independently be an alkoxycarbonyl group, an aryloxycarbonyl group or an hydrogen, alkyl, Substituted alkyl, aryl or Substituted aryl. aminocarbonyl group (such as a carbamoyl, alkylaminocar 0834. In certain instances, at least one R is hydrogen. In bonyl, dialkylaminocarbonyl or arylaminocarbonyl group)). certain instances, at least one R is alkyl. In certain instances, US 2014/O121 152 A1 May 1, 2014 at least one R is substituted alkyl. In certain instances, at least ysine, ornithine, arginine mimic, arginine homologue, argin one R is aryl. In certain instances, at least one R is substi ine truncate, arginine with varying oxidation states, lysine tuted aryl. mimic, lysine homologue, lysine truncate, and lysine with 0835. In certain instances, each of the R is hydrogen or varying oxidation states. Examples of arginine and lysine alkyl. In certain instances, all R are hydrogen. In certain mimics include arylguanidines, arylamidines (substituted instances, all R are alkyl. In certain instances, the R of benzamidines), benzylamines and (bicyclo2.2.2]octan-1-yl) N-R that is adjacent to C R is hydrogen or alkyl. In methanamine, citrulline, homocitrulline and derivatives certain instances, the RofN R that is adjacent to C R is thereof. In certain instances, R is a side chain of an amino hydrogen. In certain instances, the R of N R that is adja acid selected from arginine, lysine, homoarginine, homol cent to C R is alkyl. ysine, and ornithine. In certain instances, R is a side chain of 0836. In formulae I-IV, VII-VIII, XI, XIV, and XV. Rican an amino acid selected from arginine or lysine. In certain be selected from hydrogen, alkyl, substituted alkyl, aryl, sub instances, R is a side chain of arginine. In certain instances, stituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, R is a side chain of lysine. substituted heteroalkyl, heteroaryl, substituted heteroaryl, 10844. In certain instances, R is a side chain of an L-amino heteroarylalkyl, and substituted heteroarylalkyl. acid selected from L-arginine, L-lysine, L-homoarginine, 0837. In certain instances, in formulae I-IV, VII-VIII, XI, L-homolysine, L-ornithine, L-arginine mimic, L-arginine XIV, and XV. R is selected from hydrogen, alkyl, substituted homologue, L-arginine truncate, L-arginine with varying oxi alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, dation states, L-lysine mimic, L-lysine homologue, L-lysine heteroalkyl, substituted heteroalkyl, heteroaryl, substituted truncate, and L-lysine with varying oxidation States. In cer heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. tain instances, R is a side chain of an L-amino acid selected In certain instances, R is selected from hydrogen, alkyl, from L-arginine, L-lysine, L-homoarginine, L-homolysine, substituted alkyl, arylalkyl, substituted arylalkyl, heteroary and L-ornithine. In certain instances, R is a side chain of an lalkyl, and Substituted heteroarylalkyl. In certain instances, L-amino acid selected from L-arginine or L-lysine. In certain R is hydrogen. In certain instances, R is alkyl. In certain instances, R is a side chain of L-arginine. In certain instances, R is substituted alkyl. In certain instances, R is instances, R is a side chain of L-lysine. arylalkyl or substituted arylalkyl. In certain instances, R is heteroarylalkyl or substituted heteroarylalkyl. 0845. In certain instances, R5 represents 0838. In certain instances, in formulae I-IV, VII-VIII, XI, CHCHCH-NH(C(=NH)(NH)) O XIV, and XV. R is a side chain of an amino acid, a side chain —CHCHCHCH-NH, the configuration of the carbon of an amino acid variant, a derivative of a side chain of an atom to which R is attached corresponding with that in an amino acid, or a derivative of a side chain of an amino acid L-amino acid. variant. 0846. In formulae VI, X, XIII, and XVII, Rican be a side 0839. In formulae V, IX, XII, and XVI, R can be a side chain of an amino acid, a side chain of an amino acid variant, chain of an amino acid selected from alanine, arginine, aspar a derivative of a side chain of an amino acid, or a derivative of agine, aspartic acid, cysteine, glutamic acid, glutamine, gly a side chain of an amino acid variant that effects—C(O)—C cine, histidine, isoleucine, leucine, lysine, methionine, phe (R) N(R)—to be a GI enzyme-cleavable moiety, such as nylalanine, proline, serine, threonine, tryptophan, tyrosine, a trypsin-cleavable moiety. A GI enzyme-cleavable moiety is Valine, homoarginine, homolysine, ornithine, arginine a structural moiety that is capable of being cleaved by a GI mimic, arginine homologue, arginine truncate, arginine with enzyme. A trypsin-cleavable moiety is a structural moiety varying oxidation states, lysine mimic, lysine homologue, that is capable of being cleaved by trypsin. In certain lysine truncate, and lysine with varying oxidation states. instances, a GI enzyme-cleavable moiety comprises a 0840. In certain instances, R can be a side chain of an charged moiety that can fit into an active site of a GI enzyme amino acid selected from alanine, arginine, asparagine, aspar and is able to orient the prodrug for cleavage at a scissile bond. tic acid, cysteine, glutamic acid, glutamine, glycine, histi In certain instances, a trypsin-cleavable moiety comprises a dine, isoleucine, leucine, lysine, methionine, phenylalanine, charged moiety that can fit into an active site of trypsin and is proline, serine, threonine, tryptophan, tyrosine, and valine. able to orient the prodrug for cleavage at a scissile bond. For 0841. In certain instances, R is a side chain of an L-amino instance, the charged moiety of a GI enzyme-cleavable moi acid selected from L-alanine, L-arginine, L-asparagine, L-as ety. Such as a trypsin-cleavable moiety, can be a basic moiety partic acid, L-cysteine, L-glutamic acid, L-glutamine, gly that exists as a charged moiety at physiological pH. A deriva cine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-me tive of an amino acid or of an amino acid variant refers to a thionine, L-phenylalanine, L-proline, L-serine, L-threonine, substance that has been altered from another substance by L-tryptophan, L-tyrosine, L-valine, L-homoarginine, L-ho modification, partial Substitution, homologation, truncation, molysine, L-ornithine, L-arginine mimic, L-arginine homo or a change in oxidation state, while retaining the ability to be logue, L-arginine truncate, L-arginine with varying oxidation cleaved by a GI enzyme. states, L-lysine mimic, L-lysine homologue, L-lysine trun 10847 For example, to form a trypsin-cleavable moiety, R cate, and L-lysine with varying oxidation states. can include, but is not limited to, a side chain of lysine (Such 0842) In certain instances, R is a side chain of an L-amino as L-lysine), arginine (such as L-arginine), homolysine, acid selected from L-alanine, L-arginine, L-asparagine, L-as homoarginine, and ornithine. Other values for Rinclude, but partic acid, L-cysteine, L-glutamic acid, L-glutamine, gly are not limited to, a side chain of an arginine mimic, arginine cine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-me homologue, arginine truncate, arginine with varying oxida thionine, L-phenylalanine, L-proline, L-serine, L-threonine, tion states (for instance, metabolites), lysine mimic, lysine L-tryptophan, L-tyrosine, and L-valine. homologue, lysine truncate, and lysine with varying oxida 0843. In certain instances, R is a side chain of an amino tion states (for instance, metabolites). Examples of arginine acid selected from arginine, lysine, homoarginine, homol and lysine mimics include arylguanidines, arylamidines (Sub US 2014/O121 152 A1 May 1, 2014 44 stituted benzamidines), benzylamines, (bicyclo[2.2.2]octan 0854. In certain instances, formulae I-IV, VII-VIII, XI, 1-yl)methanamine, citrulline, homocitrulline and derivatives XIV, and XV, each R is independently selected from hydro thereof. gen, alkyl, Substituted alkyl, aryl, Substituted aryl, arylalkyl, 0848. In certain instances, R is a side chain of an amino substituted arylalkyl, heteroalkyl, substituted heteroalkyl, acid that effects - C(O) C(R) N(R) - to be a GI heteroaryl, substituted heteroaryl, heteroarylalkyl, and sub enzyme-cleavable moiety, such as a trypsin-cleavable moiety. stituted heteroarylalkyl. In certain instances, R is hydrogen. In certain instances, R is a side chain of an amino acid variant In certain instances, R is alkyl. In certain instances, R is that effects –C(O) C(R) N(R)- to be a GI enzyme substituted alkyl. In certain instances, R is arylalkyl or sub cleavable moiety, Such as a trypsin-cleavable moiety. In cer stituted arylalkyl. In certain instances, R is heteroarylalkylor tain instances, R is a derivative of a side chain of an amino substituted heteroarylalkyl. acid that effects –C(O) C(R) N(R) to be a GI 0855. In certain instances, formulae I-IV, VII-VIII, XI, enzyme-cleavable moiety, such as a trypsin-cleavable moiety. XIV, and XV, R is a side chain of an amino acid, a side chain In certain instances, R is a derivative of a side chain of an of an amino acid variant, a derivative of a side chain of an amino acid variant that effects—C(O) C(R) N(R)— to amino acid, or a derivative of a side chain of an amino acid be a GI enzyme-cleavable moiety, Such as a trypsin-cleavable variant. In certain instances, R is a side chain of an amino moiety. acid. In certain instances, R is a side chain of an amino acid 0849. In certain instances, R is a side chain of an amino variant. In certain instances, R is a derivative of a side chain acid selected from arginine, lysine, homoarginine, homol of an amino acid. In certain instances, R is a derivative of a ysine, ornithine, arginine mimic, arginine homologue, argin side chain of an amino acid variant. ine truncate, arginine with varying oxidation states, lysine 0856. In formulae V. VI, IX, X, XII, XIII, XVI, and XVI, mimic, lysine homologue, lysine truncate, and lysine with each R is a side chain of an amino acid independently varying oxidation states. In certain instances, R is a side selected from alanine, arginine, asparagine, aspartic acid, chain of an amino acid selected from arginine, lysine, cysteine, glutamic acid, glutamine, glycine, histidine, isoleu homoarginine, homolysine, and ornithine. In certain cine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and Valine. instances, R is a side chain of an amino acid selected from 0857. In certain instances, R is a side chain of an L-amino arginine or lysine. In certain instances, R is a side chain of acid selected from L-alanine, L-arginine, L-asparagine, L-as arginine. In certain instances, R is a side chain of lysine. partic acid, L-cysteine, L-glutamic acid, L-glutamine, gly 0850. In certain instances, R is a side chain of an L-amino cine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-me acid selected from L-arginine, L-lysine, L-homoarginine, thionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-homolysine, L-ornithine, L-arginine mimic, L-arginine L-tryptophan, L-tyrosine, and L-valine. homologue, L-arginine truncate, L-arginine with varying oxi 10858. In certain instances, R that is immediately adjacent dation states, L-lysine mimic, L-lysine homologue, L-lysine to R represents —H or —CH, the configuration of the truncate, and L-lysine with varying oxidation States. In cer carbon atom to which R is attached corresponding with that tain instances, R is a side chain of an L-amino acid selected in an L-amino acid. In certain instances, R that is immedi from L-arginine, L-lysine, L-homoarginine, L-homolysine, ately adjacent to R represents —H. In certain instances, R and L-ornithine. In certain instances, R is a side chain of an that is immediately adjacent to R represents —CH, the L-amino acid selected from L-arginine and L-lysine. In cer configuration of the carbon atom to which R is attached tain instances, R is a side chain of L-arginine. In certain corresponding with that in an L-amino acid. instances, R is a side chain of L-lysine. 0859. In certain instances, R that is immediately adjacent 0851. In certain instances, RS represents to R is a side chain of an amino acid selected from L-alanine CHCHCH-NH(C(-NH)(NH)) O and glycine. In certain instances, R that is immediately adja —CH2CH2CHCH-NH2, the configuration of the carbon cent to R is a side chain of L-alanine. In certain instances, R atom to which R is attached corresponding with that in an that is immediately adjacent to R is a side chain of glycine. L-amino acid. 0860 Informulae I-XVII, R' can be selected from hydro 0852. Informulae I-XVII, b is a number from Zero to 100. gen, alkyl, Substituted alkyl, acyl, Substituted acyl, alkoxy In certain instances, b is Zero to 50. In certain instances, b is carbonyl, Substituted alkoxycarbonyl, aryl, Substituted aryl, Zero to 90, 80, 70, 60, 50, 40, 30, 20, or 10. In certain arylalkyl, and substituted arylalkyl. instances, b is 100. In certain instances, b is 75. In certain 10861. In certain instances, R is hydrogen, alkyl, acyl, or instances, b is 50. In certain instances, b is 25. In certain substituted acyl. In certain instances, R is hydrogen, acyl, or instances, b is 20. In certain instances, b is 15. In certain Substituted acyl. In certain instances, R is hydrogen. In cer instances, b is 10. In certain instances, b is 9. In certain tain instances, R is alkyl. In certain instances, R is acyl or instances, b is 8. In certain instances, b is 7. In certain Substituted acyl. In certain instances, R is acyl. In certain instances, b is 6. In certain instances, b is 5. In certain instances, R is substituted acyl. In certain instances, R' can instances, b is 4. In certain instances, b is 3. In certain be acetyl, benzoyl, malonyl, piperonyl or Succinyl. In certain instances, b is 2. In certain instances, b is one. In certain instances, R' can be acetyl. In certain instances, R' can be instances, b is Zero. In certain instances, b is Zero or one. In malonyl. certain instances, b is Zero or one or two. 0862 In certain instances, a certain group of compounds 0853. In formulae I-IV, VII-VIII, XI, XIV, and XV, each are compounds of formulae I-XVII, wherein R is a side chain R can be independently selected from hydrogen, alkyl, sub of an amino acid selected from arginine and lysine and b is stituted alkyl, aryl, substituted aryl, arylalkyl, substituted ary one. In certain instances, a certain group of compounds are lalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, sub compounds of formulae I-XVII, wherein R is a side chain of stituted heteroaryl, heteroarylalkyl, and substituted an amino acid selected from arginine and lysine; R is a side heteroarylalkyl. chain of an amino acid selected from alanine and glycine; and US 2014/O121 152 A1 May 1, 2014

b is one. In certain instances, a certain group of compounds that is hydrolyzable by a protease in a manner similar to the are compounds of formulae I-XVII, wherein R is a side chain ability of a protease to hydrolyze a naturally occurring of an amino acid selected from L-arginine and L-lysine and b L-amino acid. Amino acid variants, thus, includeamino acids is one. In certain instances, a certain group of compounds are or analogs of amino acids other than the 20 naturally-occur compounds of formulae I-XVII, wherein R is a side chain of ring amino acids. Amino acid variants include synthetic an amino acid selected from L-arginine and L-lysine; R is a amino acids. side chain of an amino acid selected from L-alanine and 0869. The embodiments also include derivatives of amino glycine; and b is one. In certain instances, a certain group of acids and of amino acid variants. A derivative of an amino compounds are compounds of formulae I-XVII, wherein R acid or of an amino acid variant refers to a substance that has is a side chain of L-arginine: R is a side chain of an amino been altered from another substance by modification, partial acid selected from L-alanine and glycine; and b is one. In Substitution, homologation, truncation, or a change in oxida certain instances, a certain group of compounds are com tion state, while retaining the ability to be cleaved by a GI pounds of formulae I-XVII, wherein R is a side chain of enzyme. L-lysine; R is a side chain of an amino acid selected from 0870 Certain examples of amino acid variants include, L-alanine and glycine; and b is one. but are not limited to: 2-aminoindane-2-carboxylic acid, 0863. In certain instances, a certain group of compounds 2-aminoisobutyric acid, 4-amino-phenylalanine, 5-hydroxy are compounds of formulae I-XVII, wherein R is a side chain lysine, biphenylalanine, citruline, cyclohexylalanine, cyclo of glycine and b is one. In certain instances, a certain group of hexylglycine, diethylglycine, dipropylglycine, homoargin compounds are compounds of formulae I-XVII, wherein R ine, homocitrulline, homophenylalanine, homoproline, is a side chain of an amino acid selected from arginine and homoserine, homotyrosine, hydroxyproline, lanthionine, lysine; R is a side chain of glycine; and b is one. In certain naphthylalanine, norleucine, ornithine, phenylalanine(4- instances, a certain group of compounds are compounds of fluoro), phenylalanine(4-nitro), phenylglycine, pipecolic formulae I-XVII, wherein R is a side chain of an amino acid acid, tert-butylalanine, tert-butylglycine, tert-leucine, tet selected from L-arginine and L-lysine; R is a side chain of rahydroisoquinoline-3-carboxylic acid, C.-aminobutyric acid, glycine; and b is one. y-aminobutyric acid, 2,3-diaminoproprionic acid, phenyla 0864. In certain instances, a certain group of compounds lanine(2,3,4,5,6 pentafluoro), aminohexanoic acid and are compounds of formulae I-XVII, wherein R is a side chain derivatives thereof. ofalanine and b is one. In certain instances, a certain group of compounds are compounds of formulae I-XVII, wherein R 0871 Certain examples of amino acid variants include, is a side chain of L-alanine and b is one. In certain instances, but are not limited to, N-methyl amino acids. For example, a certain group of compounds are compounds of formulae N-methyl-alanine, N-methyl aspartic acid, N-methyl I-XVII, wherein R is a side chain of an amino acid selected glutamic acid, N-methyl-glycine (sarcosine) are N-methyl from arginine and lysine; R is a side chain of alanine; and b amino acids. is one. In certain instances, a certain group of compounds are 0872 Certain examples of amino acid variants include, compounds of formulae I-XVII, wherein R is a side chain of but are not limited to: dehydroalanine, ethionine, hypusine, an amino acid selected from L-arginine and L-lysine; R is a lanthionine, pyrrolysine, C.-aminoisobutyric acid, selenom side chain of L-alanine; and b is one. ethionine and derivatives thereof. 0865. In certain instances, a certain group of compounds 0873. Certain examples of amino acid variants include, are compounds of formulae I-XVII, wherein R is a side chain but are not limited to: (3.2-amino benzoic acid, 2-amino of L-arginine; R is a side chain of L-alanine; and b is one. In methyl benzoic acid, 2-amino-3-guanidinopropionic acid, certain instances, a certain group of compounds are com 2-amino-3-methoxy benzoic acid, 2-amino-3-ureidopropi pounds of formulae I-XVII, wherein R is a side chain of onic acid, 3-amino benzoic acid, 4-amino benzoic acid, L-arginine: R is a side chain of glycine; and b is one. In 4-amino methylbenzoic acid, 4-nitroanthranillic acid, 5-ac certain instances, a certain group of compounds are com etamido-2-aminobenzoic acid, butanoic acid (HMB), glu pounds of formulae I-XVII, wherein R is a side chain of tathione, homocysteine, statine, taurine, 3-alanine, 2-hy L-lysine; R is a side chain of L-alanine; and b is one. In droxy-4-(methylthio), (3,4)-diamino benzoic acid, (3,5)- certain instances, a certain group of compounds are com diamino benzoic acid and derivatives thereof. pounds of formulae I-XVII, wherein R is a side chain of 0874 Certain examples of amino acid variants include, L-lysine; R is a side chain of glycine; and b is one. but are not limited to: (2 amino ethyl) cysteine, 2-amino-3- ethyoxybutanoic acid, buthionine, cystathion, cysteic acid, Amino Acids Found in Prodrugs ethionine, ethoxytheorine, methylserine, N-e-e-dimethyl 0866 “Amino acid means a building block of a polypep lysine, N-(p-nitro-arginine, Saccharopine, isoserine deriva tide. As used herein, “amino acid' includes the 20 common tives thereof, and combinations thereof. naturally occurring L-amino acids and all amino acids Vari 0875 Certain examples of amino acid variants include, ants. In certain embodiments, an amino acid is a cleavable but are not limited to: 1-carnitine, selenocysteine, 1-sarcosine, Substrate for a gastrointestinal enzyme. 1-lysinol, benzoic acid, citric acid, choline, EDTA or Succinic 0867. “Naturally occurring amino acids’ means the 20 acid and derivatives thereof. common naturally occurring L-amino acids, that is, alanine, 0876 Certain examples of amino acid variants are amino arginine, asparagine, aspartic acid, cysteine, glutamic acid, alcohols. Examples of amino alcohols include, but are not glutamine, glycine, histidine, isoleucine, leucine, lysine, limited to: alaminol, indano, norephedrine, asparaginol, methionine, phenylalanine, proline, serine, threonine, tryp aspartimol, glutamol, leucinol, methioninol, phenylalaminol, tophan, tyrosine and Valine. prolinol, tryptophanol, Valinol, isoleucinol, argininol, serinol, 0868 “Amino acid variants’ means an amino acid other tyrosinol, threoninol, cysteinol, lysinol, histidinol and deriva than any of the 20 common naturally occurring L-amino acids tives thereof. US 2014/O121 152 A1 May 1, 2014 46

General Synthetic Procedures for Formulae I-XVII -continued O 0877 Representative synthetic schemes for compounds disclosed herein are shown below. Compounds of Formulae N-PG2 I-XVII can be synthesized by using the disclosed methods. HO 0878 Representative Synthetic Schemes l R5 0879 A representative synthesis for Compound S1-104 is X N NH2 S1-2O2 shown in Scheme 1. In Scheme 1, X. A ring, Y, and c are A defined herein. PG' is an amino protecting group. (Y),

Scheme 1 S1-201 O O HN YnH-PG l N-PG2H A X N N A R5 O (Y), ls S1-103 (Y), X LG S1-2O3 S1-102 O (0884. In Scheme 2, the protecting group PG' is removed from Compound S1-104 to form Compound S1-201. Condi 1s, SNH-PG tions to remove amino groups can be found in Greene and A Wuts. When PG' is a Boc group, the protecting group can be removed with acidic conditions. Such as treatment with (Y), hydrochloric acid or trifluoroacetic acid. S1-104 0885. With reference to Scheme 2, Compound S1-201 reacts with Compound S1-202 to form Compound S1-203 in a peptide coupling reaction. In certain embodiments, R is a 0880. In Scheme 1, Compound S1-102 is an active agent side chain of an amino acid and is optionally protected. Pro where the active agent comprises a functional group that is tecting groups for the side chain of amino acids are known to connected to —C(O)-LG. To form Compound S1-102, active those skilled in art and can be found in Greene and Wuts. In agent X comprises a functional group. Such as a ketone, an certain instances, the protecting group for the side chain of alcohol of a phenol, or an amide, that reacts with a reagent to arginine is a Sulfonyl-type protecting group. Such as 2.2.4.6. form a connection to —C(O)-LG. 7-pentamethyldihydrobenzofurane (Pbf). Other protecting groups include 2.2.5.7.8-pentamethylchroman (Pmc) and 0881. With continued reference to Scheme 1, LG of Com 1,2-dimethylindole-3-sulfonyl (MIS). pound S 1-102 is a leaving group. In certain instances, when 0886. A peptide coupling reaction typically employs a X is connected through an enolic oxygen, LG is a leaving conventional peptide coupling reagent and is conducted group, such as 4-nitrophenolate. under conventional coupling reaction conditions, typically in 0882. With continued reference to Scheme 1, Compound the presence of a trialkylamine, such as triethylamine or S1-102 reacts with Compound S1-103 to form Compound diisopropylethylamine (DIEA). Suitable coupling reagents S1-104. In Scheme 1, Compound S1-103 is a commercially for use include, by way of example, carbodiimides, such as available starting material. Alternatively, Compound S1-103 ethyl-3-(3-dimethylamino)propylcarbodiimide (EDC), dicy can be synthesized via a variety of different synthetic routes clohexylcarbodiimide (DCC), diisopropylcarbodiimide using commercially available starting materials and/or start (DIC) and the like, and other well-known coupling reagents, ing materials prepared by conventional synthetic methods. such as N,N'-carbonyldiimidazole, 2-ethoxy-1-ethoxycarbo nyl-1,2-dihydroquinoline (EEDQ), benzotriazol-1-yloxy-tris 0883. A representative synthesis for Compound S1-203 is (dimethylamino)phosphonium hexafluorophosphate (BOP), shown in Scheme 2. In Scheme 2. A ring, Y, c, and Rare O-(7-azabenzotriazol-1-yl)-N.N.N.N',N'-tetramethyluro defined herein. PG' and PG are amino protecting groups. nium hexafluorophosphate (HATU) and the like. Optionally, well-known coupling promoters, such as N-hydroxysuccin imide, 1-hydroxybenzotriazole (HOBT), 1-hydroxy-7-aza Scheme 2 benzotriazole (HOAT), N,N-dimethylaminopyridine O (DMAP) and the like, can be employed in this reaction. Typi cally, this coupling reaction is conducted at a temperature X l N N NH-PG ranging from about 0°C. to about 60°C. for about 1 to about A 72 hours in an inert diluent, such as THF or DMF. In certain instances, Compound S1-201 reacts with Compound S1-202 (Y), to form Compound S1-203 in the presence of HATU. 0887. A representative synthesis for Compound S1-303 is S1-104 shown in Scheme 3. In Scheme 3, R. A ring, Y. c. R. R. and R" are defined herein. PG is an amino protecting group. US 2014/O121 152 A1 May 1, 2014 47

diimide (DIC) and the like, and other well-known coupling Scheme 3 reagents, such as N,N'-carbonyldiimidazole, 2-ethoxy-1- ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), benzotria O O Zol-1-yloxy-tris(dimethylamino)phosphonium hexafluoro H phosphate (BOP), O-(7-azabenzotriazol-1-yl)-N.N.N.N',N'- l N N-PG2 tetramethyluronium hexafluorophosphate (HATU) and the A like. Optionally, well-known coupling promoters, such as X RS N R5 N-hydroxysuccinimide, 1-hydroxybenzotriazole (HOBT), (Y), 1-hydroxy-7-azabenzotriazole (HOAT), N,N-dimethylami nopyridine (DMAP) and the like, can be employed in this S1-2O3 reaction. Typically, this coupling reaction is conducted at a O temperature ranging from about 0° C. to about 60° C. for H N-R7 about 1 to about 72 hours in an inert diluent, such as THF or HO DMF. In certain instances, Compound S1-301 reacts with Compound S1-302 to form Compound S1-303 in the pres O O R6 ence of HATU. 1s, N NH2 S1-302 0890. In certain instances in Scheme 3, Compound S1-301 H -e- is reacted with Compound S1-302 with R" as a protecting group for an amino group. In these instances, the protecting A R5 group can be removed and the R group as an N-derivative (Y), group can be attached. Conditions for removal of other pro tecting groups depend on the identity of the protecting group S1-301 and are known to those skilled in the art. The conditions can O O R6 also be found in Greene and Wuts. For example, a malonyl group can be attached via a reaction with mono-tert-butyl ls NH malonate. Reaction using mono-tert-butyl malonate can be X N N N-R7 aided with use of activation reagents, such as symmetric A H H anhydrides, O-(benzotriazol-1-yl)-N.N.N',N'-tetramethylu R5 O ronium hexafluorophosphate (HBTU), dicyclohexylcarbodi (Y), imide (DCC) diisopropylcarbodiimide (DIC)/1-hydroxyben Zotriazole (HOBt), and benzotriazole-1-yl-oxytris S1-303 (dimethylamino)phosphonium hexafluorophosphate (BOP). In another example, an alkanoyl group. Such as an acetyl 0888. In Scheme 3, the protecting group PG is removed group, can be attached via a reaction with alkanoyl anhydride from Compound S1-203 to form Compound S 1-301. Condi or alkanoyl halide. 0891 Additional amino acids can be added to the com tions to remove amino groups can be found in Greene and pound through standard peptide coupling reactions as dis Wuts. When PG is a Boc group, the protecting group can be cussed herein. Removal of other protecting groups can be removed with acidic conditions. Such as treatment with performed if other protecting groups were used, such as pro hydrochloric acid or trifluoroacetic acid. tecting groups present on the R or R moiety. Conditions for 0889. With reference to Scheme 3, Compound S1-301 removal of other protecting groups depend on the identity of reacts with Compound S1-302 to form Compound S1-303 in the protecting group and are known to those skilled in the art. a peptide coupling reaction. A peptide coupling reaction typi The conditions can also be found in Greene and Wuts. cally employs a conventional peptide coupling reagent and is 0892. Additional Representative Synthetic Schemes conducted under conventional coupling reaction conditions, 0893. A representative synthesis for Compound S2-104 is typically in the presence of a trialkylamine. Such as triethy shown in Scheme 4. In Scheme 4, R'. A ring, Y, and c are lamine or diisopropylethylamine (DIEA). Suitable coupling defined herein. PG' is an amino protecting group. Although reagents for use include, by way of example, carbodiimides, the schemes herein show a morphinan structure for X in such as ethyl-3-(3-dimethylamino)propylcarbodiimide Formulae I-XVII, the entire scope of X as an active agent as (EDC), dicyclohexylcarbodiimide (DCC), diisopropylcarbo applicable to Formula I-XVII is contemplated.

Scheme 4

CH3 s" ON O O Ra S2-101

HC-O S2-100 US 2014/O121 152 A1 May 1, 2014 48

-continued CH HN YNH-PG N/ A

Ra (Y),

S2-103 NO

O HC-O O O

S2-102 -CH N

Ra K) \() HC-O O 1s YNH-PG A

(Y), S2-104

0894. In Scheme 1, Compound S2-100 is a commercially chloroformates. In Scheme 4, the activation agent Compound available starting material. Alternatively, Compound S2-100 S2-101 is 4-nitrophenyl chloroformate. Other suitable acti can be semi-synthetically derived from natural materials or Vation agents can be used prior to reaction with Compound synthesized via a variety of different synthetic routes using S2-103. 0896. With continued reference to Scheme 4, Compound commercially available starting materials and/or starting S2-102 reacts with Compound S2-103 to form Compound materials prepared by conventional synthetic methods. S2-104. In Scheme 4, Compound S2-103 is a commercially (0895. With continued reference to Scheme 4, Compound available starting material. Alternatively, Compound S2-103 S2-100 is enolized. Enolization of a ketone can be performed can be synthesized via a variety of different synthetic routes with reaction with a strong base. Such as potassium hexam using commercially available starting materials and/or start ethyldisilazide (KHMDS). The enolate of Compound S2-100 ing materials prepared by conventional synthetic methods. is then reacted with an activation agent, Such as Compound 0897. A representative synthesis for Compound S2-203 is S2-101, to form intermediate Compound S2-102. Suitable shown in Scheme 5. In Scheme 5, R". A ring, Y, c, and Rare activation agents include carbonate-forming reagents, such as defined herein. PG' and PG are amino protecting groups.

Scheme 5 CH / 3 N

Ra

O HC-O O us N NH-PGl A

(Y), S2-104 US 2014/O121 152 A1 May 1, 2014 49

-continued CH O / 3 N HO Ra KXV) HC-O O -- NH, A

(Y), S2-201

McH3 N

Ra KXV) HC-O O -- SN A

(Y), S2-2O3

(0898. In Scheme 5, the protecting group PG is removed diisopropylethylamine (DIEA). Suitable coupling reagents from Compound S2-104 to form Compound S2-201. Condi for use include, by way of example, carbodiimides, such as tions to remove amino groups can be found in Greene and ethyl-3-(3-dimethylamino)propylcarbodiimide (EDC), dicy Wuts. When PG' is a Boc group, the protecting group can be clohexylcarbodiimide (DCC), diisopropylcarbodiimide removed with acidic conditions. Such as treatment with (DIC) and the like, and other well-known coupling reagents, hydrochloric acid or trifluoroacetic acid. such as N,N'-carbonyldiimidazole, 2-ethoxy-1-ethoxycarbo nyl-1,2-dihydroquinoline (EEDQ), benzotriazol-1-yloxy-tris (0899. With reference to Scheme 5, Compound S2-201 (dimethylamino)phosphonium hexafluorophosphate (BOP), reacts with Compound S2-202 to form Compound S2-203 in O-(7-azabenzotriazol-1-yl)-N.N.N.N',N'-tetramethyluro a peptide coupling reaction. In certain embodiments, R is a nium hexafluorophosphate (HATU) and the like. Optionally, side chain of an amino acid and is optionally protected. Pro well-known coupling promoters, such as N-hydroxysuccin tecting groups for the side chain of amino acids are known to imide, 1-hydroxybenzotriazole (HOBT), 1-hydroxy-7-aza those skilled in art and can be found in Greene and Wuts. In benzotriazole (HOAT), N,N-dimethylaminopyridine certain instances, the protecting group for the side chain of (DMAP) and the like, can be employed in this reaction. Typi arginine is a Sulfonyl-type protecting group. Such as 2.2.4.6. cally, this coupling reaction is conducted at a temperature 7-pentamethyldihydrobenzofurane (Pbf). Other protecting ranging from about 0°C. to about 60°C. for about 1 to about groups include 2.2.5.7.8-pentamethylchroman (Pmc) and 72 hours in an inert diluent, such as THF or DMF. In certain 1,2-dimethylindole-3-sulfonyl (MIS). instances, Compound S2-201 reacts with Compound S2-202 0900 A peptide coupling reaction typically employs a to form Compound S2-203 in the presence of HATU. conventional peptide coupling reagent and is conducted 0901. A representative synthesis for Compound S2-303 is under conventional coupling reaction conditions, typically in shown in Scheme 6. In Scheme 6, R". A ring, Y, c, R. R. and the presence of a trialkylamine, such as triethylamine or R" are defined herein. PG is an amino protecting group. US 2014/O121 152 A1 May 1, 2014 50

Scheme 6 -CH N

Ra

KXV) O -- l N-PG HC-O O O N N N A R5 (Y), S2-2O3 CH O N/ 3 N-R HO Ra R6

S2-302 O O -e- l NH HC-O O O N YN 2 A R5 (Y). S2-301 AcHs N

Ra

HC-O O O l N N N N-R H H A R5 O (Y), S2-303

(0902. In Scheme 6, the protecting group PG is removed reagents, such as N,N'-carbonyldiimidazole, 2-ethoxy-1- from Compound S2-203 to form Compound S2-301. Condi ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), benzotria tions to remove amino groups can be found in Greene and Zol-1-yloxy-tris(dimethylamino)phosphonium hexafluoro Wuts. When PG is a Boc group, the protecting group can be phosphate (BOP), O-(7-azabenzotriazol-1-yl)-N.N.N.N',N'- removed with acidic conditions. Such as treatment with tetramethyluronium hexafluorophosphate (HATU) and the hydrochloric acid or trifluoroacetic acid. like. Optionally, well-known coupling promoters, such as N-hydroxysuccinimide, 1-hydroxybenzotriazole (HOBT), (0903. With reference to Scheme 6, Compound S2-301 reacts with Compound S2-302 to form Compound S2-303 in 1-hydroxy-7-azabenzotriazole (HOAT), N,N-dimethylami a peptide coupling reaction. A peptide coupling reaction typi nopyridine (DMAP) and the like, can be employed in this cally employs a conventional peptide coupling reagent and is reaction. Typically, this coupling reaction is conducted at a conducted under conventional coupling reaction conditions, temperature ranging from about 0° C. to about 60° C. for typically in the presence of a trialkylamine. Such as triethy about 1 to about 72 hours in an inert diluent, such as THF or lamine or diisopropylethylamine (DIEA). Suitable coupling DMF. In certain instances, Compound S2-301 reacts with reagents for use include, by way of example, carbodiimides, Compound S2-302 to form Compound S2-303 in the pres such as ethyl-3-(3-dimethylamino)propylcarbodiimide ence of HATU. (EDC), dicyclohexylcarbodiimide (DCC), diisopropylcarbo 0904. In certain instances in Scheme 6, Compound S2-301 diimide (DIC) and the like, and other well-known coupling is reacted with Compound S2-302 with R" as a protecting US 2014/O121 152 A1 May 1, 2014 group for an amino group. In these instances, the protecting synthesized via a variety of different synthetic routes using group can be removed and the R group as an N-derivative commercially available starting materials and/or starting group can be attached. Conditions for removal of other pro materials prepared by conventional synthetic methods. tecting groups depend on the identity of the protecting group and are known to those skilled in the art. The conditions can (0909. With continued reference to Scheme 7, the protect also be found in Greene and Wuts. For example, a malonyl ing group PG is removed from Compound S-401 to form group can be attached via a reaction with mono-tert-butyl Compound S-402. Conditions to remove amino groups can be malonate. Reaction using mono-tert-butyl malonate can be found in Greene and Wuts. When PG' is a Boc group, the aided with use of activation reagents, such as symmetric protecting group can be removed with acidic conditions. Such anhydrides, O-(benzotriazol-1-yl)-N.N.N',N'-tetramethylu as treatment with hydrochloric acid or trifluoroacetic acid. ronium hexafluorophosphate (HBTU), dicyclohexylcarbodi imide (DCC) diisopropylcarbodiimide (DIC)/1-hydroxyben (0910. With continued reference to Scheme 7, Compound Zotriazole (HOBt), and benzotriazole-1-yl-oxytris S-402 reacts with Compound S-403 to form Compound (dimethylamino)phosphonium hexafluorophosphate (BOP). S-404 in a peptide coupling reaction. In certain embodiments, In another example, an alkanoyl group, such as an acetyl R is a side chain of an amino acid and is optionally protected. group, can be attached via a reaction with alkanoyl anhydride Protecting groups for the side chain of amino acids are known or alkanoyl halide. to those skilled in art and can be found in Greene and Wuts. In 0905 Additional amino acids can be added to the com certain instances, the protecting group for the side chain of pound through standard peptide coupling reactions as dis arginine is a Sulfonyl-type protecting group. Such as 2.2.4.6. cussed herein. Removal of other protecting groups can be 7-pentamethyldihydrobenzofurane (Pbf). Other protecting performed if other protecting groups were used, such as pro groups include 2.2.5.7.8-pentamethylchroman (Pmc) and tecting groups present on the R or R moiety. Conditions for 1,2-dimethylindole-3-sulfonyl (MIS). removal of other protecting groups depend on the identity of 0911 A peptide coupling reaction typically employs a the protecting group and are known to those skilled in the art. The conditions can also be found in Greene and Wuts. conventional peptide coupling reagent and is conducted 0906. Additional Representative Synthetic Schemes under conventional coupling reaction conditions, typically in 0907 Representative synthesis for Compound S-404 is the presence of a trialkylamine, such as triethylamine or shown in Scheme 7. In Scheme 7. A ring, Y, c, and Rare diisopropylethylamine (DIEA). Suitable coupling reagents defined herein. PG' and PG are amino protecting groups. for use include, by way of example, carbodiimides, such as Although the schemes herein show R' and Ras being hydro ethyl-3-(3-dimethylamino)propylcarbodiimide (EDC), dicy gen and a being one, the entire scope of R', R, and a as clohexylcarbodiimide (DCC), diisopropylcarbodiimide applicable to Formula I-XVII is contemplated. (DIC) and the like, and other well-known coupling reagents, such as N,N'-carbonyldiimidazole, 2-ethoxy-1-ethoxycarbo nyl-1,2-dihydroquinoline (EEDQ), benzotriazol-1-yloxy-tris Scheme 7 (dimethylamino)phosphonium hexafluorophosphate (BOP), O-(7-azabenzotriazol-1-yl)-N.N.N.N',N'-tetramethyluro HN YNH-PG nium hexafluorophosphate (HATU) and the like. Optionally, A -e- well-known coupling promoters, such as N-hydroxysuccin imide, 1-hydroxybenzotriazole (HOBT), 1-hydroxy-7-aza (Y), benzotriazole (HOAT), N,N-dimethylaminopyridine S-401 (DMAP) and the like, can be employed in this reaction. Typi O cally, this coupling reaction is conducted at a temperature H ranging from about 0°C. to about 60°C. for about 1 to about N-PG2 72 hours in an inert diluent, such as THF or DMF. In certain HO instances, Compound S-402 reacts with Compound S-403 to R5 form Compound S-404 in the presence of HATU. HN NH2 A S-403 0912. A representative synthesis for Compound S-503 is shown in Scheme 5. In Scheme 8. A ring, Y, c, and Rare (Y), defined herein. PG is an amino protecting group.

S-402 O Scheme 8 H N-PG2 N- N H A R5 N N-PG2 S-5O1 A H O C (Y), R5 S-404 O ON S-404 0908. In Scheme 7, Compound S-401 is a commercially S-502 available starting material. Alternatively, Compound S-401 can be semi-synthetically derived from natural materials or US 2014/O121 152 A1 May 1, 2014 52

-continued phosphate (HBTU), dicyclohexylcarbodiimide (DCC) diiso O O propylcarbodiimide (DIC)/1-hydroxybenzotriazole (HOBt), H and benzotriazole-1-yl-oxytris(dimethylamino)phospho l N-PG? nium hexafluorophosphate (BOP). In another example, an A H alkanoyl group, such as an acetyl group, can be attached via a R5 reaction with alkanoyl anhydride or alkanoyl halide. (Y), 0917 Removal of other protecting groups can be per formed if other protecting groups were used, such as protect S-503 ing groups present on the R or R moiety. Conditions for removal of other protecting groups depend on the identity of (0913. In Scheme 8, Compound S-501 is reacted with an the protecting group and are known to those skilled in the art. activation agent, such as Compound S-502. Suitable activa The conditions can also be found in Greene and Wuts. tion agents include carbonate-forming reagents, such as chlo (0918 Enzyme Inhibitors roformates. In Scheme 8, the activation agent Compound 0919. The enzyme capable of cleaving the enzyme-cleav S-502 is 4-nitrophenyl chloroformate. Other suitable activa able moiety of an active agent prodrug can be a peptidase, also tion agents can be used prior to reaction with Compound called a protease. In certain embodiments, the enzyme is an S-404. enzyme located in the gastrointestinal (GI) tract, i.e., a gas 0914 With continued reference to Scheme 8, activated trointestinal enzyme, or a GI enzyme. The enzyme can be a Compound S-501 reacts with Compound S-404 to form Com digestive enzyme Such as a gastric, intestinal, pancreatic or pound S-503. In Scheme 8, Compound S-501 is a commer brush border enzyme or enzyme of GI microbial flora, such as cially available starting material. Alternatively, Compound those involved in peptide hydrolysis. Examples include a S-501 can be synthesized via a variety of different synthetic pepsin, such as pepsin A or pepsin B; a trypsin; a chymot routes using commercially available starting materials and/or rypsin; an elastase; a carboxypeptidase, such as carboxypep starting materials prepared by conventional synthetic meth tidase A or carboxypeptidase B; an aminopeptidase (such as ods. aminopeptidase Noraminopeptidase A.; an endopeptidase; an exopeptidase; a dipeptidylaminopeptidase such as dipeptidy laminopeptidase IV: a dipeptidase; a tripeptidase; or an Scheme 9 enteropeptidase. In certain embodiments, the enzyme is a O O cytoplasmic protease located on or in the GI brush border. In H certain embodiments, the enzyme is trypsin. Accordingly, in Gpioid-01ul SN N N-PG2 certain embodiments, the corresponding composition is A -e- administered orally to the patient. R5 0920. The disclosure provides for a composition compris (Y), ing a GI enzyme inhibitor. Such an inhibitor can inhibit at S-503 least one of any of the GI enzymes disclosed herein. An O O example of a GI enzyme inhibitor is a protease inhibitor, such H as a trypsin inhibitor. l N-R7 0921. As used herein, the term “GI enzyme inhibitor” A H refers to any agent capable of inhibiting the action of a GI R5 enzyme on a substrate. The ability of an agent to inhibit a GI enzyme can be measured using assays well known in the art. (Y), 0922. In certain embodiments, the GI enzyme capable of S-601 cleaving the enzyme-cleavable moiety may be a protease. The disclosure provides for inhibitors of proteases. 0915. Additional amino acids can be added to the com 0923 Proteases can be classified as exopeptidases or pound through standard peptide coupling reactions as dis endopeptidases. Examples of exopeptidases include ami cussed herein. For example, additional amino acids can be nopeptidase and carboxypeptidase (A, B, or Y). Examples of added to Compound S-503 with removal of protecting group endopeptidases include trypsin, chymotrypsin, elastase, pep PG and addition of amino acids through standard peptide sin, and papain. The disclosure provides for inhibitors of coupling reactions. Additional amino acids can be also added exopeptidase and endopeptidase. to Compound S-404 before reaction with Compound S-501 0924. In some embodiments, the enzyme is a digestive with removal of protecting group PG and addition of amino enzyme of a protein. The disclosure provides for inhibitors of acids through standard peptide coupling reactions. digestive enzymes. A gastric phase involves stomach (0916. In Scheme 9, Compound S-503 is converted to enzymes, such as pepsin. An intestinal phase involves Compound S-601 with R" as an N-derivative group. Condi enzymes in the Small intestine duodenum, Such as trypsin, tions for removal of protecting groups depend on the identity chymotrypsin, elastase, carboxypeptidase A, and carbox of the protecting group and are known to those skilled in the ypeptidase B. An intestinal brush border phase involves art. The conditions can also be found in Greene and Wuts. In enzymes in the Small intestinal brush border, Such as ami certain instances, for example, a malonyl group can be nopeptidase N. aminopeptidase A, endopeptidases, dipepti attached via a reaction with mono-tert-butyl malonate. Reac dases, dipeptidylaminopeptidase, and dipeptidylaminopepti tion using mono-tert-butyl malonate can be aided with use of dase IV. An intestinal intracellular phase involves activation reagents, such as symmetric anhydrides, O-(ben intracellular peptidases, such as dipeptidases (i.e. iminopep Zotriazol-1-yl)-N.N.N',N'-tetramethyluronium hexafluoro tidase) and aminopeptidase. US 2014/O121 152 A1 May 1, 2014

0925. In certain embodiments, the enzyme inhibitor in the can be measured using assays well known in the art. For disclosed compositions is a peptidase inhibitor or protease example, in a typical assay, one unit corresponds to the inhibitor. In certain embodiments, the enzyme is a digestive amount of inhibitor that reduces the trypsin activity by one enzyme Such as a gastric, pancreatic or brush border enzyme, benzoyl-L-arginine ethyl ester unit (BAEE-U). One BAEE-U Such as those involved in peptide hydrolysis. Examples is the amount of enzyme that increases the absorbance at 253 include pepsin, trypsin, chymotrypsin, colipase, elastase, nm by 0.001 perminute at pH 7.6 and 25°C. See, for example, aminopeptidase N. aminopeptidase A, dipeptidylaminopep K. Ozawa, M. Laskowski, 1966, J. Biol. Chem. 241,3955 and tidase IV, tripeptidase or enteropeptidase. Y. Birk, 1976, Meth. Enzymol. 45,700. In certain instances, 0926 Proteases can be inhibited by naturally occurring a trypsin inhibitor can interact with an active site of trypsin, peptide or protein inhibitors, or by small molecule naturally such as the 51 pocket and the S3/4 pocket. The 51 pocket has occurring or synthetic inhibitors. Examples of protein or pep an aspartate residue which has affinity for positively charged tide inhibitors that are protease inhibitors include, but are not moiety. The S3/4 pocket is a hydrophobic pocket. The disclo limited to, al-antitrypsin from human plasma, aprotinin, Sure provides for specific trypsin inhibitors and non-specific trypsin inhibitor from soybean (SBTI), Bowman-Birk Inhibi serine protease inhibitors. tor from soybean (BBSI), trypsin inhibitor from egg white (ovomucoid), chromostatin, and potato-derived carboxypep 0929. There are many trypsin inhibitors known in the art, tidase inhibitor. Examples of small molecule irreversible both those specific to trypsin and those that inhibit trypsin and inhibitors that are protease inhibitors include, but are not other proteases such as chymotrypsin. The disclosure pro limited to, TPCK (1-chloro-3-tosylamido-4-phenyl-2-bu vides for trypsin inhibitors that are proteins, peptides, and tanone), TLCK (1-chloro-3-tosylamido-7-amino-2-hep small molecules. The disclosure provides for trypsin inhibi tone), and PMSF (phenylmethylsulfonyl fluoride). Examples tors that are irreversible inhibitors or reversible inhibitors. of small molecule irreversible inhibitors that are protease The disclosure provides for trypsin inhibitors that are com inhibitors include, but are not limited to benzamidine, apixa petitive inhibitors, non-competitive inhibitors, or uncompeti ban, camo.stat, 3,4-dichloroisocoumarin, e-aminocaprionic tive inhibitors. The disclosure provides for natural, synthetic acid, amastatin, lysianadioic acid, 1,10-phenanthroline, cys or semi-synthetic trypsin inhibitors. teamine, and bestatin. Other examples of Small molecule 0930 Trypsin inhibitors can be derived from a variety of inhibitors are Compound 101, Compound 102, Compound animal or Vegetable sources: for example, soybean, corn, lima 103, Compound 104, Compound 105, Compound 106, Com and other beans, squash, Sunflower, bovine and other animal pound 107, Compound 108, Compound 109 and Compound pancreas and lung, chicken and turkey egg white, Soy-based 110. infant formula, and mammalian blood. Trypsin inhibitors can 0927. The following table shows examples of gastrointes also be of microbial origin: for example, antipain; see, for tinal (GI) proteases, examples of their corresponding Sub example, H. Umezawa, 1976, Meth. Enzymol. 45, 678. strates, and examples of corresponding inhibitors. 0931. In one embodiment, the trypsin inhibitor is derived from soybean. Trypsin inhibitors derived from soybean (Gly cine max) are readily available and are considered to be safe Table of Examples of GI Proteases and Corresponding for human consumption. They include, but are not limited to, Substrates and Inhibitors SBTI, which inhibits trypsin, and Bowman-Birk inhibitor, GI Protease Substrates Inhibitors which inhibits trypsin and chymotrypsin. Such trypsin inhibi Trypsin Arg, LyS, TLCK, Benzamidine, tors are available, for example from Sigma-Aldrich, St. positively Apixaban, Bowman Birk Louis, Mo., USA. charged residues Chymotrypsin Phe, Tyr, Trp, e-Aminocaprionic 0932. A trypsin inhibitor can be an arginine mimic or bulky TPCK hydrophobic Bowman-Birk lysine mimic, either natural or synthetic compound. In certain residues embodiments, the trypsin inhibitor is an arginine mimic or a Pepsin Leu, Phe, Trp, Pepstatin, PMSF lysine mimic, wherein the arginine mimic or lysine mimic is Tyr Carboxypeptidase B Arg, Lys Potato-derived inhibitor, a synthetic compound. As used herein, an arginine mimic or Lysianadioic acid lysine mimic can include a compound capable of binding to Carboxypeptidase. A not Arg, Lys Potato-derived inhibitor, 1,10 phenanthroline the P' pocket of trypsin and/or interfering with trypsin active Elastase Ala, Gly, Ser, C1-antitrypsin, site function. The arginine or lysine mimic can be a cleavable Small neutral 3,4-dichlorocoumarin or non-cleavable moiety. residues Aminopeptidase All free N- Bestatin, Amastatin 0933 Examples of trypsin inhibitors, which are arginine terminal AA mimics and/or lysine mimics, include, but not limited to, arylguanidine, benzamidine, 3,4-dichloroisocoumarin, diiso propylfluorophosphate, gabexate mesylate, and phenyl Trypsin Inhibitors methanesulfonyl fluoride, or Substituted versions or analogs 0928. As used herein, the term “trypsin inhibitor refers to thereof. In certain embodiments, trypsin inhibitors comprise any agent capable of inhibiting the action of trypsin on a a covalently modifiable group. Such as a chloroketone moiety, substrate. The term “trypsin inhibitor also encompasses salts an aldehyde moiety, or an epoxide moiety. Other examples of of trypsin inhibitors. The ability of an agent to inhibit trypsin trypsin inhibitors are aprotinin, camo.stat and pentamidine. US 2014/O121 152 A1 May 1, 2014 54

0934. Other examples of trypsin inhibitors include com- 0940 wherein: pounds of formula: (0941 Q is C(O) COOH or NH-Q°-Q7-SO, CHs, where (0942 Q is —(CH.). COOH: Q O 3 (0943 Q7 is —(CH), CH: 1. \- 0944) Q is NH; O r HN1 \ (0945 n is a number from Zero to two: N- O 0946 o is zero or one: 0947 p is an integer from one to three; and H 0948 r is an integer from one to three. O N NH2, 0949 Other examples of trypsin inhibitors include com pounds of formula: NH

0935 wherein: NH 0936. Q is selected from O-Q or -Q-COOH, where Q is C-C alkyl: NH2, 0937. Q is N or CH; and Q 0938. Q is aryl or substituted aryl. 0939 Certain trypsin inhibitors include compounds offor mula: 0950 wherein: 0951 Q is C(O) COOH or NH-Q°-Q7-SO, (Q) NH CHs, where Cs 22 0952 Q is -(CH2). COOH: 5 0953 Q7 is -(CH), CHs; and Q pi NH 0954 p is an integer from one to three; and 0955 r is an integer from one to three. 0956 Certain trypsin inhibitors include the following:

Compound101 l (naphthalene-2-(S)-ethyl 4-(5-guanidino-2- Sulfonamido)pentanoyl)piperazine O O 1-carboxylate O1. r HN1\, V Nu O H O N NH2 NH

Compound (S)-ethyl 4-(5-guanidino-2-(2,4,6- 102 l pentanoyl)piperazine-1-carboxylatetriisopropylphenylsulfonamido) O O 1.- ... 1 S O r HN1 \O

H - O S. N NH2

US 2014/O121 152 A1 May 1, 2014

-continued Compound O OH (S)-5-(4- 108 NH carbamimidoylbenzylamino)-5- oxo-4-((R)-4-phenyl-2- (phenylmethylsulfonamido) O NH2 butanamido)pentanoic acid

s1 N AV H O O O

Compound N NH2 6-carbamimidoylnaphthalen-2-yl 4 109 s (diaminomethyleneamino)benzoate O NH2 HN O O

NH 44'-(pentane-1,5- Compound110 N-1-1-9 diylbis(oxy))dibenzimidamide HN NH2

NH NH

0957. A description of methods to prepare Compound 0962 R and R' each represents independently a 101, Compound 102, Compound 103, Compound 104, Com hydrogen atom or a C- alkyl group, R represents a pound 105, Compound 107, and Compound 108 is provided group selected from the following formulae: in PCT 0958 International Publication Number WO 2010/ 045599A1, published 22 Apr. 2010, which is hereby incor Rt 11 Rill, O porated by reference in its entirety. Compound 106, Com / pound 109, and Compound 110 can be obtained CON CON coS)-R commercially (Sigma-Aldrich, St. Louis, Mo., USA.). y: n Rt 12 0959. In certain embodiments, the trypsin inhibitor is SBTI, BBSI, Compound 101, Compound 106, Compound 108, Compound 109, or Compound 110. In certain embodi 0963 wherein R', R'' and R' each represents indepen ments, the trypsin inhibitor is camoStat. dently 0960. In certain embodiments, the trypsin inhibitor is a 0964 (1) a hydrogen atom, compound of formula T-I: 0965 (2) a phenyl group, 0966 (3) a C alkyl group substituted by a phenyl group, (T-1) O o 0967 (4) a Co alkyl group, HN M 0968 (5) a Coalkoxyl group, 0969 (6) a Coalkenyl group having 1 to 3 double bonds, HN () - 0970 (7) a C- alkynyl group having 1 to 2 triple bonds, 0971 (8) a group of formula: R' C(O)XR', wherein 0972 wherein R' represents a single bond or a Cs 0961. A represents a group of the following formula: alkylene group, 0973 X represents an oxygen atom or an NH-group, - CC and A s R9 Rt 10 0974) R' represents a hydrogen atom, a C- alkyl group, a phenyl group or a C alkyl group Substituted by a phenyl group, or US 2014/O121 152 A1 May 1, 2014 57

0975 (9) a C-7 cycloalkyl group; tuted amino, hydroxyl, cyano and —(CH), C(O)—O— 0976 the structure (CH), C(O) N. R'R'', wherein each m is indepen dently zero to 2; and R" and R' are independently selected from hydrogen and C alkyl. (0986. In certain embodiments, in formula T-II, R" is O guanidino or amidino. represents a 4-7 membered monocyclic hetero-ring contain 0987. In certain embodiments, in formula T-II, R' is ing 1 to 2 nitrogen or oxygen atoms, (CH), C(O)-O-(CH), C(O)-N-R'R'', 0977) R' represents a hydrogenatom, a C, alkyl group wherein m is one and R'' and R" are methyl. Substituted by a phenyl group or a group of formula: 0988. In certain embodiments, the trypsin inhibitor is a COOR'', wherein R'7 represents a hydrogen atom, a Ca compound of formula T-III: alkyl group or a C alkyl group Substituted by a phenyl group; 0978 provided that R', R'' and R' do not represent (T-III) simultaneously hydrogen atoms; HN 0979 or nontoxic salts, acid addition salts or hydrates pi thereof. y-X -()--w-e HN 0980. In certain embodiments, the trypsin inhibitor is a compound selected from the following:

H3C O O HN H 21 ( K ) N-( )-d HN COOCHs HC O O o HN 2 / N-(H )-d HN COOC2H5 O O COOCHs. O HN 21 N HN-( y-d HN O O HN 21 N N O HN)--( )- C2H5OOC -U)

0981. In certain embodiments, the trypsin inhibitor is a wherein compound of formula T-II: 0989 X is NH; 0990 n is zero or one: 0991 L' is selected from –C(O)-O-, - O C(O)–: HN (T-II) —O—(CH), O—; –OCH Ar’ CHO : 2 C(O) NR' ; and NR. C(O) ; X-X. Ril 0992 R is selected from hydrogen, C alkyl, and sub HN stituted C. alkyl; 0993 Ar' and Ar' are independently a substituted or unsubstituted aryl group; 0982 wherein 0994 m is a number from 1 to 3; and 0983 X is NH; 0995) R' is selected from hydrogen, halogen, nitro, alkyl, 0984 n is zero or one; and Substituted alkyl, alkoxy, carboxyl, alkoxycarbonyl, acyl, 0985) R' is selected from hydrogen, halogen, nitro, alkyl, aminoacyl, guanidine, amidino, carbamide, amino, Substi Substituted alkyl, alkoxy, carboxyl, alkoxycarbonyl, acyl, tuted amino, hydroxyl, cyano and —(CH), C(O)—O— aminoacyl, guanidine, amidino, carbamide, amino, Substi (CH), C(O) N. R'R'', wherein each m is indepen US 2014/O121 152 A1 May 1, 2014

dently zero to 2; and R" and R' are independently selected assimilation that can be used in combination with a prodrug from hydrogen and C alkyl. disclosed herein comprising an amino acid of alanine, argin 0996. In certain embodiments, in formula T-III, R’ is ine, asparagine, aspartic acid, cysteine, glutamic acid, guanidino or amidino. In certain embodiments, in formula glutamine, glycine, histidine, isoleucine, leucine, lysine, T-III, R’ is —(CH), C(O)-O-(CH), C(O) N methionine, phenylalanine, proline, serine, threonine, tryp R'R'', wherein m is one and R'' and R' are methyl. tophan, tyrosine, or valine or amino acid variants thereof. 0997. In certain embodiments, the trypsin inhibitor is a compound of formula T-IV: Combinations of Prodrug and Trypsin Inhibitor 1011. As disclosed above, the present disclosure also pro (T-IV) vides pharmaceutical compositions, and their methods of use, NH where the pharmaceutical compositions comprise an active agent prodrug, that provides controlled release of an active HN l agent, and a trypsin inhibitor that interacts with the trypsin that mediates the -controlled release of the active agent from HNX-x-( )--v-x. NH2 the prodrug so as to attenuate enzymatic cleavage of the prodrug. wherein 1012 The embodiments provide a pharmaceutical com 0998 each X is NH; position, which comprises a trypsin inhibitor and a compound 0999 each n is independently zero or one; of general Formulae I-XIV, or a pharmaceutically acceptable 1000 L' is selected from –C(O)-O-, - O C(O)–: salt thereof. The embodiments provide a pharmaceutical —O-(CH2). O—; –OCH Ar’ CHO : composition, which comprises a trypsin inhibitor and a com C(O) NR' ; and NR. C(O) ; pound of general Formulae XV-XVII, or a pharmaceutically 1001) R' is selected from hydrogen, Ce alkyl, and sub acceptable salt thereof. stituted C. alkyl; 1013 The embodiments provide a pharmaceutical com 1002 Ar' and Ar' are independently a substituted or position, which comprises a compound of Formulae T-I to unsubstituted aryl group; and T-IV and a compound of general Formulae I-XIV, or a phar 1003 m is a number from 1 to 3. maceutically acceptable salt thereof. The embodiments pro 1004. In certain embodiments, in formula T-IV. Ar' or vide a pharmaceutical composition, which comprises a com Ar' is phenyl. pound of Formulae T-I to T-IV and a compound of general 1005. In certain embodiments, in formula T-IV. Ar' or Formulae XV-XVII, or a pharmaceutically acceptable salt Ar' is naphthyl. thereof. The embodiments provide a pharmaceutical compo sition, which comprises Compound 109 and a compound of 1006. In certain embodiments, the trypsin inhibitor is general Formulae I-XIV, or a pharmaceutically acceptable Compound 109. salt thereof. The embodiments provide a pharmaceutical 1007. In certain embodiments, the trypsin inhibitor is composition, which comprises Compound 109 and a com pound of general Formulae XV-XVII, or a pharmaceutically O acceptable salt thereof. 1014 Certain embodiments provide for a combination of a O ouls N1 compound of Formula I and a trypsin inhibitor, shown in the table below. Certain embodiments provide for a combination O of a compound of Formula II and a trypsin inhibitor, shown in NH O the table below. Certain embodiments provide for a combi nation of a compound of Formulae III-VI and a trypsin inhibi H -- tor, shown in the table below. Certain embodiments provide 2 H for a combination of a compound of Formulae VII-X and a trypsin inhibitor, shown in the table below. Certain embodi 1008. In certain embodiments, the trypsin inhibitor is ments provide for a combination of a compound of Formulae Compound 110 or a bis-arylamidine variant thereof; see, for XI-XIII and a trypsin inhibitor, shown in the table below. example, J. D. Geratz, M. C.-F. Cheng and R. R. Tidwell Certain embodiments provide for a combination of a com (1976) J. Med. Chem. 19,634-639. pound of Formula XIV and a trypsin inhibitor, shown in the 1009. It will be appreciated that the pharmaceutical com table below. Certain embodiments provide for a combination position according to the embodiments may further comprise of a compound of Formulae XV-XVII and a trypsin inhibitor, one or more additional trypsin inhibitors. shown in the table below. Certain embodiments provide for a 1010. It is to be appreciated that the invention also combination of a compound of Formula XIV and a trypsin includes inhibitors of other enzymes involved in protein inhibitor, shown in the table below.

Prodrug of Prodrug of Prodrug of Prodrug of Formula XI- Prodrug of Prodrug of Prodrug of Formula II and Formula III-VI Formula VII-X XIII and Formula XIV. Formula XV-XVII Formula I and Trypsin and Trypsin and Trypsin Trypsin and Trypsin and Trypsin Trypsin Inhibitor Inhibitor Inhibitor Inhibitor Inhibitor Inhibitor Inhibitor

SBTI SBTI SBTI SBTI SBTI SBTI SBTI BBSI BBSI BBSI BBSI BBSI BBSI BBSI Compound 101 Compound 101 Compound 101 Compound 101 Compound 101 Compound 101 Compound 101 Compound 106 Compound 106 Compound 106 Compound 106 Compound 106 Compound 106 Compound 106 US 2014/O121 152 A1 May 1, 2014

-continued Prodrug of Prodrug of Prodrug of Prodrug of Formula XI- Prodrug of Prodrug of Prodrug of Formula II and Formula III-VI Formula VII-X XIII and Formula XIV. Formula XV-XVII Formula I and Trypsin and Trypsin and Trypsin Trypsin and Trypsin and Trypsin Trypsin Inhibitor Inhibitor Inhibitor Inhibitor Inhibitor Inhibitor Inhibitor Compound 108 Compound 108 Compound 108 Compound 108 Compound 108 Compound 108 Compound 108 Compound 109 Compound 109 Compound 109 Compound 109 Compound 109 Compound 109 Compound 109 Compound 110 Compound 110 Compound 110 Compound 110 Compound 110 Compound 110 Compound 110

Combinations of Active Agent Prodrugs and Other Drugs pain. Accordingly, the present disclosure provides methods of treating or preventing pain in a Subject, the methods involving 1015 The disclosure provides for an active agent prodrug administering to the Subject a disclosed composition. The of the embodiments and a further prodrug or drug included in present disclosure provides for a disclosed composition for a pharmaceutical composition. use in therapy or prevention or as a medicament. The present 1016 For example, such a prodrug or drug would provide disclosure also provides the use of a disclosed composition additional analgesia, e.g., a synergistic effect, or other ben for the manufacture of a medicament, especially for the efits. Examples include opioids, opioid prodrugs, acetami manufacture of a medicament for the treatment or prevention nophen, non-steroidal anti-inflammatory drugs (NSAIDs) of pain. and other analgesics. In one embodiment, two or more opioid 1022. The compositions of the present disclosure can be agonist prodrugs and/or drugs (e.g., a morphine prodrug or used in the treatment or prevention of pain including, but not drug and an oxycodone prodrug of the embodiments), each at limited to include, acute pain, chronic pain, neuropathic pain, a Sub-analgesic dose, would be combined to provide a syner acute traumatic pain, arthritic pain, osteoarthritic pain, rheu gistic response leading to effective analgesia with reduced matoid arthritic pain, muscular skeletal pain, post-dental Sur side effects. In one embodiment, an opioid agonist prodrug or gical pain, dental pain, myofascial pain, cancer pain, visceral drug would be combined with an opioidantagonist prodrug or pain, diabetic pain, muscular pain, post-herpetic neuralgic drug. Other examples include drugs or prodrugs that have pain, chronic pelvic pain, endometriosis pain, pelvic inflam benefits other than, or in addition to, analgesia. The embodi matory pain and childbirth related pain. Acute pain includes, ments provide a pharmaceutical composition, which com but is not limited to, acute traumatic pain or post-Surgical prises an opioid prodrug and acetaminophen and optionally pain. Chronic pain includes, but is not limited to, neuropathic comprises an enzyme inhibitor. Also included are pharma pain, arthritic pain, osteoarthritic pain, rheumatoid arthritic ceutically acceptable salts thereof. pain, muscular skeletal pain, dental pain, myofascial pain, 1017. In certain embodiments, the enzyme inhibitor is cancer pain, diabetic pain, visceral pain, muscular pain, post selected from SBTI, BBSI, Compound 101, Compound 106, herpetic neuralgic pain, chronic pelvic pain, endometriosis Compound 108, Compound 109, and Compound 110. In pain, pelvic inflammatory pain and back pain. certain embodiments, the enzyme inhibitor is camo.stat. 1023 The present disclosure provides use of a compound 1018. In certain embodiments, a pharmaceutical compo of Formulae I-XVII in the treatment of pain. The present sition can comprise an active agent prodrug, a non-opioid disclosure provides use of a compound of Formulae I-XVII in drug and at least one opioid or opioid prodrug. the prevention of pain. 1024. The present disclosure provides use of a compound Pharmaceutical Compositions and Methods of Use of Formulae I-XVII in the manufacture of a medicament for 1019. The present disclosure provides a composition, such treatment of pain. The present disclosure provides use of a as a pharmaceutical composition, which comprises a com compound of Formulae I-XVII in the manufacture of a medi pound of Formulae I-XVII. Such a pharmaceutical composi cament for prevention of pain. tion according to the embodiments can further comprise a 1025. In another aspect, the embodiments provide a pharmaceutically acceptable carrier. The composition is con method of treating pain in a patient in need thereof, which veniently formulated in a form suitable for oral (including comprises administering to Sucha patient an effective amount buccal and Sublingual) administration, for example as a tab of a pharmaceutical composition as described herein. In let, capsule, thin film, powder, Suspension, Solution, syrup, another aspect, the embodiments provide a method of pre dispersion or emulsion. The composition can contain compo venting pain in a patient in need thereof, which comprises nents conventional in pharmaceutical preparations, e.g. one administering to Such a patient an effective amount of a phar or more carriers, binders, lubricants, excipients (e.g., to maceutical composition as described herein. impart controlled release characteristics), pH modifiers, 1026. The amount of composition disclosed herein to be Sweeteners, bulking agents, coloring agents or further active administered to a patient to be effective (i.e. to provide blood agents. levels of an active agent sufficient to be effective in the treat 1020 Patients can be humans, and also other mammals, ment or prophylaxis of pain) will depend upon the bioavail Such as livestock, Zoo animals and companion animals. Such ability of the particular composition, the susceptibility of the as a cat, dog or horse. particular composition to enzyme activation in the gut, as well 1021. In another aspect, the embodiments provide a phar as other factors, such as the species, age, weight, sex, and maceutical composition as described herein for use in the condition of the patient, manner of administration and judg treatment of pain. The pharmaceutical composition accord ment of the prescribing physician. If the composition also ing to the embodiments is useful, for example, in the treat comprises a trypsin inhibitor, the amount of composition ment of a patient Suffering from, or at risk of Suffering from disclosed herein to be administered to a patient would also US 2014/O121 152 A1 May 1, 2014 60 depend on the amount and potency of trypsin inhibitor present Representative Embodiments of Dose Units of Prodrug and in the composition. In general, the dose can be such that the GI Enzyme Inhibitor Having a Desired Pharmacokinetic active agent prodrug is in the range of from 0.01 milligrams Profile per kilogram to 20 milligrams prodrug per kilogram (mg/kg) 1032 The embodiments include a composition that com body weight. For example, an active agent prodrug can be prises (a) an active agent prodrug of Formulae I-XVII, which administered at a dose equivalent to administering free active comprises an active agent covalently bound to a promoiety agent in the range of from 0.02-mg/kg to 0.5-mg/kg body comprising a GI enzyme-cleavable moiety, wherein cleavage weight or 0.01-mg/kg to 10-mg/kg body weight or 0.01-mg/ of the GI enzyme-cleavable moiety by a GI enzyme mediates kg to 2-mg/kg body weight. In one embodiment, the compo release of an active agent, and (b) a GI enzyme inhibitor that sition can be administered at a dose such that the level of the interacts with the GI enzyme that mediates enzymatically active agent achieved in the blood is in the range of from 0.5 controlled release of the active agent from the prodrug fol ng/ml to 200 ng/ml. In one embodiment, the composition can lowing ingestion of the composition. In one embodiment, the be administered at a dose such that the level of the active agent GI enzyme is trypsin, the GI enzyme-cleavable moiety is a achieved in the blood is in the range of from 0.5 ng/ml to 20 trypsin-cleavable moiety, and the GI enzyme inhibitor is a ng/ml. In one embodiment, the composition can be adminis trypsin inhibitor. tered at a dose such that the level of the active agent achieved 1033. The embodiments include a dose unit comprising a in the blood is in the range of from 0.5 ng/ml to 10 ng/ml. composition, Such as a pharmaceutical composition, com prising an active agent prodrug of Formulae I-XVII and a GI 1027. As disclosed above, the present disclosure also pro enzyme inhibitor, where the active agent prodrug of Formulae vides a pharmaceutical composition that comprises an active I-XVII and GI enzyme inhibitor are present in the dose unit in agent prodrug of Formulae I-XVII and a trypsin inhibitor. an amount effective to provide for a pre-selected pharmaco Such an active agent prodrug comprises a promoiety com kinetic (PK) profile following ingestion. In further embodi prising a trypsin-cleavable moiety that, when cleaved, facili ments, the pre-selected PK profile comprises at least one PK tates release of active agent. parameter value that is less than the PK parameter value of active agent released following ingestion of an equivalent 1028. The present disclosure provides use of a compound dosage of an active agent prodrug of Formulae I-XVII in the of Formulae I-XVII and a trypsin inhibitor in the treatment of absence of inhibitor. In further embodiments, the PK param pain. The present disclosure provides use of a compound of eter value is selected from an active agent Cmax value, an Formulae I-XVII and a trypsin inhibitor in the prevention of active agent exposure value, and a (l/active agent Tmax) pa1n. value. 1034. In certain embodiments, the dose unit provides for a 1029. The present disclosure provides use of a compound pre-selected PK profile following ingestion of at least two of Formulae I-XVII and a trypsin inhibitor in the manufacture dose units. In related embodiments, the pre-selected PK pro of a medicament for treatment of pain. The present disclosure file of such dose units is modified relative to the PK profile provides use of a compound of Formulae I-XVII and a trypsin followingingestion of an equivalent dosage of an active agent inhibitor in the manufacture of a medicament for prevention prodrug of Formulae I-XVII without inhibitor. In related of pain. embodiments. Such a dose unit provides that ingestion of an 1030. In another aspect, the embodiments provide a increasing number of the dose units provides for a linear PK method of treating pain in a patient in need thereof, which profile. In related embodiments, such a dose unit provides that comprises administering to Such apatient an effective amount ingestion of an increasing number of the dose units provides of a pharmaceutical composition comprising a compound of for a nonlinear PK profile. In related embodiments, the PK Formulae I-XVII and a trypsin inhibitor. In another aspect, parameter value of the PK profile of such a dose unit is the embodiments provide a method of preventing pain in a selected from an active agent Cmax value, a (1/active agent patient in need thereof, which comprises administering to Tmax) value, and an active agent exposure value. 1035. The embodiments include methods for treating a Such a patient an effective amount of a pharmaceutical com patient comprising administering any of the compositions, position comprising a compound of Formulae I-XVII and a Such as pharmaceutical compositions, comprising an active trypsin inhibitor. agent prodrug of Formulae I-XVII and a GI enzyme inhibitor 1031. In such pharmaceutical compositions, the amount of or dose units described hereinto a patient in need thereof. The a trypsin inhibitor to be administered to the patient to be embodiments include methods to reduce side effects of a effective (i.e. to attenuate release of an active agent when therapy comprising administering any of such compositions, administration of a compound disclosed herein alone would e.g., pharmaceutical compositions, or dose units described lead to overexposure of the active agent) will depend upon the herein, to a patient in need thereof. The embodiments include effective dose of the particular prodrug and the potency of the methods of improving patient compliance with a therapy particular inhibitor, as well as other factors, such as the spe prescribed by a clinician comprising directing administration cies, age, weight, sex and condition of the patient, manner of of any of Such compositions, e.g., pharmaceutical composi administration and judgment of the prescribing physician. In tions, or dose units described herein, to a patient in need general, the dose of inhibitor can be in the range of from 0.05 thereof. Such embodiments can provide for improved patient mg to 50 mg per mg of prodrug disclosed herein. In a certain compliance with a prescribed therapy as compared to patient embodiment, the dose of inhibitor can be in the range of from compliance with a prescribed therapy using drug and/or using 0.001 mg to 50 mg per mg of prodrug disclosed herein. In one prodrug without inhibitor as compared to prodrug with embodiment, the dose of inhibitor can be in the range of from inhibitor. 0.01 nanomoles to 100 micromoles per micromole of prodrug 1036. The embodiments include methods of reducing risk disclosed herein. of unintended overdose of an active agent comprising direct US 2014/O121 152 A1 May 1, 2014

ing administration of any of such compositions, e.g., pharma the GI enzyme inhibitor indicates the GI enzyme inhibitor ceutical compositions, or dose units described herein, to a and prodrug of Formulae I-XVII are suitable for formulation patient in need of treatment. in a dose unit. 1037. The embodiments include methods of making a dose unit comprising combining an active agent prodrug of Dose Units of Prodrug and Inhibitor Having a Desired Formulae I-XVII and a GI enzyme inhibitor in a dose unit, Pharmacokinetic Profile wherein the active agent prodrug of Formulae I-XVII and GI 1043. The present disclosure provides dose units of pro enzyme inhibitor are present in the dose unit in an amount drug and inhibitor that can provide for a desired pharmaco effective to attenuate release of active agent from the active kinetic (PK) profile. Dose units can provide a modified PK agent prodrug of Formulae I-XV. profile compared to a reference PK profile as disclosed 1038. The embodiments include methods of deterring herein. It will be appreciated that a modified PK profile can misuse or abuse of multiple dose units of an active agent provide for a modified pharmacodynamic (PD) profile. Inges prodrug of Formulae I-XVII comprising combining an active tion of multiples of such a dose unit can also provide a desired agent prodrug of Formulae I-XVII and a GI enzyme inhibitor PK profile. in a dose unit, wherein the active agent prodrug of Formulae 1044) Unless specifically stated otherwise, “dose unit as I-XVII and GI enzyme inhibitor are present in the dose unit in used herein refers to a combination of a GI enzyme-cleavable an amount effective to attenuate release of an active agent prodrug (e.g., trypsin-cleavable prodrug) and a GI enzyme from the active agent prodrug of Formulae I-XVII such that inhibitor (e.g., a trypsin inhibitor). A 'single dose unit' is a ingestion of multiples of dose units by a patient does not single unit of a combination of a GI enzyme-cleavable pro provide a proportional release of the active agent. In further drug (e.g., trypsin-cleavable prodrug) and a GI enzyme embodiments, release of drug is decreased compared to inhibitor (e.g., trypsin inhibitor), where the single dose unit release of drug by an equivalent dosage of prodrug in the provide a therapeutically effective amount of drug (i.e., a absence of inhibitor. Sufficient amount of drug to effect a therapeutic effect, e.g., a 1039. One embodiment is a method for identifying a GI dose within the respective drugs therapeutic window, or enzyme inhibitor and prodrug of Formulae I-XVII suitable therapeutic range). “Multiple dose units’ or “multiples of a for formulation in a dose unit. Such a method can be con dose unit' or a “multiple of a dose unit” refers to at least two ducted as, for example, an in vitro assay, an in vivo assay, or single dose units. an ex vivo assay. In one embodiment, the GI enzyme inhibitor 1045. As used herein, a “PK profile” refers to a profile of is a trypsin inhibitor. drug concentration in blood or plasma. Such a profile can be a relationship of drug concentration over time (i.e., a “con 1040. The embodiments include methods for identifying a centration-time PK profile') or a relationship of drug concen GI enzyme inhibitor and prodrug of Formulae I-XVII suitable tration versus number of doses ingested (i.e., a "concentra for formulation in a dose unit comprising combining a pro tion-dose PK profile'.) A PK profile is characterized by PK drug of Formulae I-XVII, a GI enzyme inhibitor, and a GI parameters. enzyme in a reaction mixture, and detecting prodrug conver 1046. As used herein, a “PK parameter” refers to a mea Sion, wherein a decrease in prodrug conversion in the pres Sure of drug concentration in blood or plasma, Such as: 1) ence of the GI enzyme inhibitor as compared to prodrug 'drug Cmax', the maximum concentration of drug achieved conversion in the absence of the GI enzyme inhibitor indi in blood or plasma; 2) "drug Tmax', the time elapsed follow cates the GI enzyme inhibitor and prodrug of Formulae ing ingestion to achieve Cmax; and 3) "drug exposure', the I-XVII are suitable for formulation in a dose unit. total concentration of drug present in blood or plasma over a 1041. The embodiments include methods for identifying a selected period of time, which can be measured using the area GI enzyme inhibitor and prodrug of Formulae I-XVII suitable under the curve (AUC) of a time course of drug release over for formulation in a dose unit comprising administering to an a selected period of time (t). Modification of one or more PK animal a GI enzyme inhibitor and prodrug of Formulae parameters provides for a modified PK profile. I-XVII and detecting prodrug conversion, wherein a decrease 1047 For purposes of describing the features of dose units in active agent conversion in the presence of the GI enzyme of the present disclosure, “PK parameter values” that define a inhibitor as compared to active agent conversion in the PK profile include drug Cmax (e.g., active agent Cmax), total absence of the GI enzyme inhibitor indicates the GI enzyme drug exposure (e.g., area under the curve) (e.g., active agent inhibitor and prodrug of Formulae I-XVII are suitable for exposure) and 1/(drug Tmax) (Such that a decreased 1/Tmax formulation in a dose unit. In certain embodiments, adminis is indicative of a delay in Tmax relative to a reference Tmax) tering comprises administering to the animal increasing doses (e.g., 1/active agent Tmax). Thus a decrease in a PK param of inhibitor co-dosed with a selected fixed dose of prodrug. eter value relative to a reference PK parameter value can Detecting prodrug conversion can facilitate identification of a indicate, for example, a decrease in drug Cmax, a decrease in dose of inhibitor and a dose of prodrug that provides for a drug exposure, and/or a delayed Tmax. pre-selected pharmacokinetic (PK) profile. Such methods can 1048 Dose units of the present disclosure can be adapted be conducted as, for example, an in vivo assay or an ex vivo to provide for a modified PK profile, e.g., a PK profile that is assay. different from that achieved from dosing a given dose of 1042. The embodiments include methods for identifying a prodrug in the absence of inhibitor (i.e., without inhibitor). GI enzyme inhibitor and prodrug of Formulae I-XVII suitable For example, dose units can provide for at least one of for formulation in a dose unit comprising administering to an decreased drug Cmax, delayed drug Tmax and/or decreased animal tissue a GI enzyme inhibitor and prodrug of Formulae drug exposure compared to ingestion of a dose of prodrug in I-XVII and detecting prodrug conversion, wherein a decrease the same amount but in the absence of inhibitor. Such a in prodrug conversion in the presence of the GI enzyme modification is due to the inclusion of an inhibitor in the dose inhibitor as compared to prodrug conversion in the absence of unit. US 2014/O121 152 A1 May 1, 2014 62

1049. As used herein, “a pharmacodynamic (PD) profile' concentration following ingestion of the same amount of refers to a profile of the efficacy of a drug in a patient (or prodrug with inhibitor. In this example, the dose unit provides subject or user), which is characterized by PD parameters. a PK profile having a decreased drug Cmax, decreased drug “PD parameters' include “drug Emax” (the maximum drug exposure, and a delayed drug Tmax (i.e., decreased (1/drug efficacy), "drug EC50' (the concentration of drug at 50% of Tmax) relative to ingestion of the same dose of prodrug the Emax), and side effects. without inhibitor. 1050 FIG. 1 is a schematic illustrating an example of the 1057 Panel C of FIG. 2 provides another example of a effect of increasing inhibitor concentrations upon the PK dose unit having a modified concentration-time PK profile. parameter drug Cmax for a fixed dose of prodrug. At low As in Panel A, the solid line represents drug concentration concentrations of inhibitor, there may be no detectable effect over time in blood or plasma following ingestion of prodrug on drug release, as illustrated by the plateau portion of the plot without inhibitor, while the dashed line represents drug con of drug Cmax (Y axis) versus inhibitor concentration (X centration following ingestion of the same amount of prodrug axis). As inhibitor concentration increases, a concentration is with inhibitor. In this example, the dose unit provides a PK reached at which drug release from prodrug is attenuated, profile having a delayed drug Tmax (i.e., decreased (1/drug causing a decrease in, or Suppression of drug Cmax. Thus, Tmax) relative to ingestion of the same dose of prodrug the effect of inhibitor upon a prodrug PK parameter for a dose without inhibitor. unit of the present disclosure can range from undetectable, to 1058 Dose units that provide for a modified PK profile moderate, to complete inhibition (i.e., no detectable drug (e.g., a decreased drug Cmax and/or delayed drug Tmax as release). compared to, a PK profile of drug or a PK profile of prodrug 1051. A dose unit can be adapted to provide for a desired without inhibitor), find use in tailoring of drug dose according PK profile (e.g., a concentration-time PK profile) following to a patient’s needs (e.g., through selection of a particular ingestion of a single dose. A dose unit can be adapted to dose unit and/or selection of a dosage regimen), reduction of provide for a desired PK profile (e.g., a concentration-dose side effects, and/or improvement in patient compliance (as PK profile) followingingestion of multiple dose units (e.g., at compared to side effects or patient compliance associated least 2, at least 3, at least 4 or more dose units). with drug or with prodrug without inhibitor). As used herein, 1052) Dose Units Providing Modified PK Profiles “patient compliance' refers to whether a patient follows the 1053 A combination of a prodrug and an inhibitor in a direction of a clinician (e.g., a physician) including ingestion dose unit can provide a desired (or “pre-selected') PK profile of a dose that is neither significantly above nor significantly (e.g., a concentration-time PK profile) following ingestion of below that prescribed. Such dose units also reduce the risk of a single dose. The PK profile of such a dose unit can be misuse, abuse or overdose by a patient as compared to Such characterized by one or more of a pre-selected drug Cmax, a risk(s) associated with drug or prodrug without inhibitor. For pre-selected drug Tmax or a pre-selected drug exposure. The example, dose units with a decreased drug Cmax provide less PK profile of the dose unit can be modified compared to a PK reward for ingestion than does a dose of the same amount of profile achieved from the equivalent dosage of prodrug in the drug, and/or the same amount of prodrug without inhibitor. absence of inhibitor (i.e., a dose that is the same as the dose 1059 Dose Units Providing Modified PK Profiles Upon unit except that it lacks inhibitor). Ingestion of Multiple Dose Units 1054) A modified PK profile can have a decreased PK 1060 A dose unit of the present disclosure can be adapted parameter value relative to a reference PK parameter value to provide for a desired PK profile (e.g., a concentration-time (e.g., a PK parameter value of a PK profile following inges PK profile or concentration-dose PK profile) following inges tion of a dosage of prodrug that is equivalent to a dose unit tion of multiples of a dose unit (e.g., at least 2, at least 3, at except without inhibitor). For example, a dose unit can pro least 4, or more dose units). A concentration-dose PK profile vide for a decreased drug Cmax, decreased drug exposure, refers to the relationship between a selected PK parameter and/or delayed drug Tmax. and a number of single dose units ingested. Such a profile can 1055 FIG.2 presents schematic graphs showing examples be dose proportional, linear (a linear PK profile) or nonlinear of modified concentration-time PK profiles of a single dose (a nonlinear PK profile). A modified concentration-dose PK unit. Panel A is a schematic of drug concentration in blood or profile can be provided by adjusting the relative amounts of plasma (Y axis) following a period of time (X axis) after prodrug and inhibitor contained in a single dose unit and/or by ingestion of prodrug in the absence or presence of inhibitor. using a different prodrug and/or inhibitor. The solid, top line in Panel A provides an example of drug 1061 FIG. 3 provides schematics of examples of concen concentration following ingestion of prodrug without inhibi tration-dose PK profiles (exemplified by drug Cmax, Y axis) tor. The dashed, lower line in Panel A represents drug con that can be provided by ingestion of multiples of a dose unit centration following ingestion of the same dose of prodrug (X axis) of the present disclosure. Each profile can be com with inhibitor. Ingestion of inhibitor with prodrug provides pared to a concentration-dose PK profile provided by increas for a decreased drug Cmax relative to the drug Cmax that ing doses of drug alone, where the amount of drug in the blood results from ingestion of the same amount of prodrug in the or plasma from one dose represents atherapeutically effective absence of inhibitor. Panel A also illustrates that the total drug amount equivalent to the amount of drug released into the exposure following ingestion of prodrug with inhibitor is also blood or plasma by one dose unit of the disclosure. Such a decreased relative to ingestion of the same amount of prodrug “drug alone. PK profile is typically dose proportional, having without inhibitor. a forty-five degree angle positive linear slope. It is also to be 1056 Panel B of FIG. 2 provides another example of a appreciated that a concentration-dose PK profile resulting dose unit having a modified concentration-time PK profile. fromingestion of multiples of a dose unit of the disclosure can As in Panel A, the Solid top line represents drug concentration also be compared to other references, such as a concentration over time in blood or plasma following ingestion of prodrug dose PK profile provided by ingestion of an increasing num without inhibitor, while the dashed lower line represents drug ber of doses of prodrug without inhibitor wherein the amount US 2014/O121 152 A1 May 1, 2014

of drug released into the blood or plasma by a single dose of linear with a negative slope. Thus drug Cmax decreases as the prodrug in the absence of inhibitor represents a therapeuti number of dose units ingested increases. cally effective amount equivalent to the amount of drug 1068 Dose units that provide for concentration-dose PK released into the blood or plasma by one dose unit of the profiles when multiples of a dose unit are ingested find use in disclosure. tailoring of a dosage regimento provide a therapeutic level of 1062. As illustrated by the relationship between prodrug released drug while reducing the risk of overdose, misuse, or and inhibitor concentration in FIG. 2, a dose unit can include abuse. Such reduction in risk can be compared to a reference, inhibitor in an amount that does not detectably affect drug e.g., to administration of drug alone or prodrug alone. In one release following ingestion. Ingestion of multiples of Such a embodiment, risk is reduced compared to administration of a dose unit can provide a concentration-dose PK profile Such drug or prodrug that provides a proportional concentration that the relationship between number of dose units ingested dose PK profile. A dose unit that provides for a concentration and PK parameter value is linear with a positive slope, which dose PK profile can reduce the risk of patient overdose is similar to, for example, a dose proportional PK profile of through inadvertent ingestion of dose units above a pre increasing amounts of prodrug alone. Panel A of FIG. 3 scribed dosage. Such a dose unit can reduce the risk of patient depicts such a profile. Dose units that provide a concentra misuse (e.g., through self-medication). Such a dose unit can tion-dose PK profile having such an undetectable change in discourage abuse through deliberate ingestion of multiple drug Cmax in vivo compared to the profile of prodrug alone dose units. For example, a dose unit that provides for a bipha can find use in thwarting enzyme conversion of prodrug from sic concentration-dose PK profile can allow for an increase in a dose unit that has sufficient inhibitor to reduce or prevent in drug release for a limited number of dose units ingested, after vitro cleavage of the enzyme-cleavable prodrug by its respec which an increase in drug release withingestion of more dose tive enzyme. units is not realized. In another example, a dose unit that 1063 Panel B in FIG.3 represents a concentration-dose provides for a concentration-dose PK profile of zero slope can PK profile such that the relationship between the number of allow for retention of a similar drug release profile regardless dose units ingested and a PK parameter value is linear with of the number of dose units ingested. positive slope, where the profile exhibits a reduced slope 1069 Ingestion of multiples of a dose unit can provide for relative to panel A. Such a dose unit provides a profile having adjustment of a PK parameter value relative to that of inges a decreased PK parameter value (e.g., drug Cmax) relative to tion of multiples of the same dose (either as drug alone or as a reference PK parameter value exhibiting dose proportion a prodrug) in the absence of inhibitor Such that, for example, ality. ingestion of a selected number (e.g., 2, 3, 4 or more) of a 1064 Concentration-dose PK profiles following ingestion single dose unit provides for a decrease in a PK parameter of multiples of a dose unit can be non-linear. Panel C in FIG. value compared to ingestion of the same number of doses in 3 represents an example of a non-linear, biphasic concentra the absence of inhibitor. tion-dose PK profile. In this example, the biphasic concen 1070 Pharmaceutical compositions include those having tration-dose PK profile contains a first phase over which the an inhibitor to provide for protection of a therapeutic com concentration-dose PK profile has a positive rise, and then a pound from degradation in the GI tract. Inhibitor can be second phase over which the relationship between number of combined with a drug (i.e., not a prodrug) to provide for dose units ingested and a PK parameter value (e.g., drug protection of the drug from degradation in the GI system. In Cmax) is relatively flat (substantially linear with Zero slope). this example, the composition of inhibitor and drug provide For Such a dose unit, for example, drug Cmax can be for a modified PK profile by increasing a PK parameter. increased for a selected number of dose units (e.g. 2, 3, or 4 Inhibitor can also be combined with a prodrug that is suscep dose units). However, ingestion of additional dose units does tible to degradation by a GI enzyme and has a site of action not provide for a significant increase in drug Cmax. outside the GI tract. In this composition, the inhibitor protects 1065 Panel D in FIG.3 represents another example of a ingested prodrug in the GI tract prior to its distribution outside non-linear, biphasic concentration-dose PK profile. In this the GI tract and cleavage at a desired site of action. example, the biphasic concentration-dose PK profile is char acterized by a first phase over which the concentration-dose Methods Used to Define Relative Amounts of Prodrug and PK profile has a positive rise and a second phase over which Inhibitor in a Dose Unit the relationship between number of dose units ingested and a 1071 Dose units that provide for a desired PK profile, PK parameter value (e.g., drug Cmax) declines. Dose units such as a desired concentration-time PK profile and/or a that provide this concentration-dose PK profile provide for an desired concentration-dose PK profile, can be made by com increase in drug Cmax for a selected number of ingested dose bining a prodrug and an inhibitor in a dose unit in relative units (e.g., 2, 3, or 4 dose units). However, ingestion of further amounts effective to provide for release of drug that provides additional dose units does not provide for a significant for a desired drug PK profile following ingestion by a patient. increase in drug Cmax and instead provides for decreased 1072 Prodrugs can be selected as suitable for use in a dose drug Cmax. unit by determining the GI enzyme-mediated drug release 1066 Panel E in FIG.3 represents a concentration-dose competency of the prodrug. This can be accomplished in PK profile in which the relationship between the number of vitro, in vivo or ex vivo. dose units ingested and a PK parameter (e.g., drug Cmax) is 1073. In vitro assays can be conducted by combining a linear with Zero slope. Such dose units do not provide for a prodrug with a GI enzyme (e.g., trypsin) in a reaction mixture. significant increase or decrease in drug Cmax with ingestion The GI enzyme can be provided in the reaction mixture in an of multiples of dose units. amount Sufficient to catalyze cleavage of the prodrug. Assays 1067 Panel F in FIG. 3 represents a concentration-dose are conducted under Suitable conditions, and optionally may PK profile in which the relationship between number of dose be under conditions that mimic those found in a GI tract of a units ingested and a PK parameter value (e.g., drug Cmax) is Subject, e.g., human. "Prodrug conversion” refers to release US 2014/O121 152 A1 May 1, 2014 64 of drug from prodrug. Prodrug conversion can be assessed by tor are suitable for formulation in a dose unit. Such a method detecting a level of a product of prodrug conversion (e.g., can be an in Vivo assay; for example, the prodrug and GI released drug) and/or by detecting a level of prodrug that is enzyme inhibitor can be administered orally. Such a method maintained in the presence of the GI enzyme. Prodrug con can also be an ex vivo assay; for example, the prodrug and GI version can also be assessed by detecting the rate at which a enzyme inhibitor can be administered orally or to a tissue, product of prodrug conversion occurs or the rate at which Such as an intestine, that is at least temporarily exposed. prodrug disappears. An increase in released drug, or a Detection can occur in the blood or plasma or respective decrease in prodrug, indicate prodrug conversion has tissue. As used herein, tissue refers to the tissue itself and can occurred. Prodrugs that exhibit an acceptable level of prodrug also refer to contents within the tissue. conversion in the presence of the GI enzyme within an accept 1079. One embodiment is a method for identifying a pro able period of time are suitable for use in a dose unit in drug and a GI enzyme inhibitor suitable for formulation in a combination with an inhibitor of the GI enzyme that is shown dose unit wherein the method comprises administering a pro to mediate prodrug conversion. drugandagastrointestinal (GI) enzyme inhibitor to an animal 1074. In vivo assays can assess the suitability of a prodrug tissue that has removed from an animal and detecting prodrug for use in a dose unit by administration of the prodrug to an conversion. In one embodiment, a decrease in prodrug con animal (e.g., a human or non-human animal, e.g., rat, dog. version in the presence of the GI enzyme inhibitor as com pig, etc.). Such administration can be enteral (e.g., oral pared to prodrug conversion in the absence of the GI enzyme administration). Prodrug conversion can be detected by, for inhibitor indicates the prodrug and GI enzyme inhibitor are example, detecting a product of prodrug conversion (e.g., suitable for formulation in a dose unit. released drug or a metabolite of released drug) or detecting 1080. In vitro assays can be conducted by combining a prodrug in blood or plasma of the animal at a desired time prodrug, an inhibitor and a GI enzyme in a reaction mixture. point(s) following administration. The GI enzyme can be provided in the reaction mixture in an 1075) Ex vivo assays, such as a gut loop or inverted gut amount Sufficient to catalyze cleavage of the prodrug, and loop assay, can assess the Suitability of a prodrug for use in a assays conducted under Suitable conditions, optionally under dose unit by, for example, administration of the prodrug to a conditions that mimic those found in a GI tract of a Subject, ligated section of the intestine of an animal. Prodrug conver e.g., human. Prodrug conversion can be assessed by detecting sion can be detected by, for example, detecting a product of a level of a product of prodrug conversion (e.g., released drug) prodrug conversion (e.g., released drug or a metabolite of and/or by detecting a level of prodrug maintained in the released drug) or detecting prodrug in the ligated gut loop of presence of the GI enzyme. Prodrug conversion can also be the animalata desired time point(s) following administration. assessed by detecting the rate at which a product of prodrug 1076 Inhibitors are generally selected based on, for conversion occurs or the rate at which prodrug disappears. example, activity in interacting with the GI enzyme(s) that Prodrug conversion that is modified in the presence of inhibi mediate release of drug from a prodrug with which the inhibi tor as compared to a level of prodrug conversion in the tor is to be co-dosed. Such assays can be conducted in the absence of inhibitor indicates the inhibitor is suitable for presence of enzyme either with or without prodrug. Inhibitors attenuation of prodrug conversion and for use in a dose unit. can also be selected according to properties such as half-life Reaction mixtures having a fixed amount of prodrug and in the GI system, potency, avidity, affinity, molecular size increasing amounts of inhibitor, or a fixed amount of inhibitor and/or enzyme inhibition profile (e.g., steepness of inhibition and increasing amounts of prodrug, can be used to identify curve in an enzyme activity assay, inhibition initiation rate). relative amounts of prodrug and inhibitor which provide for a Inhibitors for use in prodrug-inhibitor combinations can be desired modification of prodrug conversion. selected through use of in vitro, in Vivo and/or ex vivo assays. 1081. In vivo assays can assess combinations of prodrugs 1077 One embodiment is a method for identifying a pro and inhibitors by co-dosing of prodrug and inhibitor to an drug and a GI enzyme inhibitor suitable for formulation in a animal. Such co-dosing can be enteral. “Co-dosing refers to dose unit wherein the method comprises combining a prodrug administration of prodrug and inhibitor as separate doses or a (e.g., an active agent prodrug), a GI enzyme inhibitor (e.g., a combined dose (i.e., in the same formulation). Prodrug con trypsin inhibitor), and a GI enzyme (e.g., trypsin) in a reaction version can be detected by, for example, detecting a product mixture and detecting prodrug conversion. Such a combina of prodrug conversion (e.g., released drug or drug metabolite) tion is tested for an interaction between the prodrug, inhibitor or detecting prodrug in blood or plasma of the animal at a and enzyme, i.e., tested to determine how the inhibitor will desired time point(s) following administration. Combina interact with the enzyme that mediates enzymatically-con tions of prodrug and inhibitor can be identified that provide trolled release of the drug from the prodrug. In one embodi for a prodrug conversion level that yields a desired PK profile ment, a decrease in prodrug conversion in the presence of the as compared to, for example, prodrug without inhibitor. GI enzyme inhibitor as compared to prodrug conversion in 1082 Combinations of relative amounts of prodrug and the absence of the GI enzyme inhibitor indicates the prodrug inhibitor that provide for a desired PK profile can be identified and GI enzyme inhibitor are suitable for formulation in a dose by dosing animals with a fixed amount of prodrug and unit. Such a method can be an in vitro assay. increasing amounts of inhibitor, or with a fixed amount of 1078. One embodiment is a method for identifying a pro inhibitor and increasing amounts of prodrug. One or more PK drug and a GI enzyme inhibitor suitable for formulation in a parameters can then be assessed, e.g., drug Cmax, drug Tmax, dose unit wherein the method comprises administering to an and drug exposure. Relative amounts of prodrug and inhibitor animal a prodrug and a GI enzyme inhibitor and detecting that provide for a desired PK profile are identified as amounts prodrug conversion. In one embodiment, a decrease in pro of prodrug and inhibitor for use in a dose unit. The PK profile drug conversion in the presence of the GI enzyme inhibitor as of the prodrug and inhibitor combination can be, for example, compared to prodrug conversion in the absence of the GI characterized by a decreased PK parameter value relative to enzyme inhibitor indicates the prodrug and GI enzyme inhibi prodrug without inhibitor. A decrease in the PK parameter US 2014/O121 152 A1 May 1, 2014 value of an inhibitor-to-prodrug combination (e.g., a decrease Methods for Manufacturing, Formulating, and Packaging in drug Cmax, a decrease in 1/drug Tmax (i.e., a delay in drug Dose Units Tmax) or a decrease in drug exposure) relative to a corre 1087. Dose units of the present disclosure can be made sponding PK parameter value following administration of using manufacturing methods available in the art and can be prodrug without inhibitor can be indicative of an inhibitor-to of a variety of forms suitable for enteral (including oral, prodrug combination that can provide a desired PK profile. buccal and Sublingual) administration, for example as a tab Assays can be conducted with different relative amounts of let, capsule, thin film, powder, Suspension, Solution, syrup, inhibitor and prodrug. dispersion or emulsion. The dose unit can contain compo nents conventional in pharmaceutical preparations, e.g. one 1083. In vivo assays can be used to identify combinations or more carriers, binders, lubricants, excipients (e.g., to of prodrug and inhibitor that provide for dose units that pro impart controlled release characteristics), pH modifiers, fla vide for a desired concentration-dose PK profile following Voring agents (e.g., Sweeteners), bulking agents, coloring ingestion of multiples of the dose unit (e.g., at least 2, at least agents or further active agents. Dose units of the present 3, at least 4 or more). Ex vivo assays can be conducted by disclosure can include can include an enteric coating or other direct administration of prodrug and inhibitor into a tissue component(s) to facilitate protection from Stomach acid, and/or its contents of an animal. Such as the intestine, includ where desired. ing by introduction by injection into the lumen of a ligated 1088 Dose units can be of any suitable size or shape. The intestine (e.g., a gut loop, or intestinal loop, assay, or an dose unit can be of any shape Suitable for enteral administra inverted gut assay). An ex vivo assay can also be conducted by tion, e.g., ellipsoid, lenticular, circular, rectangular, cylindri excising a tissue and/or its contents from an animal and intro cal, and the like. ducing prodrug and inhibitor into Such tissues and/or con 1089 Dose units provided as dry dose units can have a tentS. total weight of from about 1 microgram to about 1 gram, and can be from about 5 micrograms to 1.5 grams, from about 50 1084. For example, a dose of prodrug that is desired for a micrograms to 1 gram, from about 100 micrograms to 1 gram, single dose unit is selected (e.g., an amount that provides an from 50 micrograms to 750 milligrams, and may be from efficacious plasma drug level). A multiple of single dose units about 1 microgram to 2 grams. for which a relationship between that multiple and a PK 1090 Dose units can comprise components in any relative parameter to be tested is then selected. For example, if a amounts. For example, dose units can be from about 0.1% to concentration-dose PK profile is to be designed for ingestion 99% by weight of active ingredients (i.e., prodrug and inhibi of 2, 3, 4, 5, 6, 7, 8, 9 or 10 dose units, then the amount of tor) per total weight of dose unit (0.1% to 99% total combined prodrug equivalent to ingestion of that same number of dose weight of prodrug and inhibitor pertotal weight of single dose units is determined (referred to as the “high dose”). The unit). In some embodiments, dose units can be from 10% to multiple of dose units can be selected based on the number of 50%, from 20% to 40%, or about 30% by weight of active ingested pills at which drug Cmax is modified relative to ingredients per total weight dose unit. ingestion of the single dose unit. If, for example, the profile is 1091 Dose units can be provided in a variety of different to provide for abuse deterrence, then a multiple of 10 can be forms and optionally provided in a manner Suitable for Stor selected, for example. A variety of different inhibitors (e.g., age. For example, dose units can be disposed within a con from a panel of inhibitors) can be tested using different rela tainer Suitable for containing a pharmaceutical composition. tive amounts of inhibitor and prodrug. Assays can be used to The container can be, for example, a bottle (e.g., with a identify suitable combination(s) of inhibitor and prodrug to closure device, such as a cap), a blister pack (e.g., which can obtain a single dose unit that is therapeutically effective, provide for enclosure of one or more dose units per blister), a wherein such a combination, when ingested as a multiple of vial, flexible packaging (e.g., sealed Mylar or plastic bags), an dose units, provides a modified PK parameter compared to ampule (for single dose units in Solution), a dropper, thin film, ingestion of the same multiple of drug or prodrug alone a tube and the like. (wherein a single dose of either drug or prodrug alone releases 1092 Containers can include a cap (e.g., Screw cap) that is into blood or plasma the same amount of drug as is released removably connected to the container over an opening by a single dose unit). through which the dose units disposed within the container can be accessed. 1085. Increasing amounts of inhibitor are then co-dosed to 1093 Containers can include a seal which can serve as a animals with the high dose of prodrug. The dose level of tamper-evident and/or tamper-resistant element, which seal is inhibitor that provides a desired drug Cmax following inges disrupted upon access to a dose unit disposed within the tion of the high dose of prodrug is identified and the resultant container. Such seal elements can be, for example, a frangible inhibitor-to-prodrug ratio determined. element that is broken or otherwise modified upon access to a 1086 Prodrug and inhibitor are then co-dosed in amounts dose unit disposed within the container. Examples of Such equivalent to the inhibitor-to-prodrug ratio that provided the frangible seal elements include a seal positioned over a con desired result at the high dose of prodrug. The PK parameter tainer opening such that access to a dose unit within the value of interest (e.g., drug Cmax) is then assessed. If a container requires disruption of the seal (e.g., by peeling desired PK parameter value results following ingestion of the and/or piercing the seal). Examples of frangible seal elements single dose unit equivalent, then single dose units that provide include a frangible ring disposed around a container opening for a desired concentration-dose PK profile are identified. For and in connection with a cap Such that the ring is broken upon example, where a Zero dose linear profile is desired, the drug opening of the cap to access the dose units in the container. Cmax following ingestion of a single dose unit does not 1094) Dry and liquid dose units can be placed in a con increase significantly following ingestion of a multiple num tainer (e.g., bottle or package, e.g., a flexible bag) of a size and ber of the single dose units. configuration adapted to maintain stability of dose units over US 2014/O121 152 A1 May 1, 2014 66 a period during which the dose units are dispensed into a combination thereof. For example, the formulation in the first prescription. For example, containers can be sized and con chamber can be liquid and the formulation in the second figured to contain 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or chamber can be dry, both can be dry, or both can be liquid. more single dry or liquid dose units. The containers can be 1100 Dose units that provide for controlled release of sealed or resealable. The containers can packaged in a carton prodrug, of inhibitor, or of both prodrug and inhibitor are (e.g., for shipment from a manufacturer to a pharmacy or contemplated by the present disclosure, where “controlled other dispensary). Such cartons can be boxes, tubes, or of release' refers to release of one or both of prodrug and inhibi other configuration, and may be made of any material (e.g., tor from the dose unit over a selected period of time and/or in cardboard, plastic, and the like). The packaging system and/ a pre-selected manner. or containers disposed therein can have one or more affixed labels (e.g., to provide information Such as lot number, dose Methods of Use of Dose Units unit type, manufacturer, and the like). 1101 Dose units are advantageous because they find use 1095. The container can include a moisture barrier and/or in methods to reduce side effects and/or improve tolerability light barrier, e.g., to facilitate maintenance of Stability of the of drugs to patients in need thereof by, for example, limiting active ingredients in the dose units contained therein. Where a PK parameter as disclosed herein. The present disclosure the dose unit is a dry dose unit, the container can include a thus provides methods to reduce side effects by administering desiccant pack which is disposed within the container. The a dose unit of the present disclosure to a patient in need so as container can be adapted to contain a single dose unit or to provide for a reduction of side effects as compared to those multiples of a dose unit. The container can include a dispens associated with administration of drug and/or as compared to ing control mechanism, such as a lock out mechanism that administration of prodrug without inhibitor. The present dis facilitates maintenance of dosing regimen. closure also provides methods to improve tolerability of 1096. The dose units can be provided in solidorsemi-solid drugs by administering a dose unit of the present disclosure to form, and can be a dry dose unit. “Dry dose unit refers to a a patient in need so as to provide for improvement in toler dose unit that is in other than in a completely liquid form. ability as compared to administration of drug and/or as com Examples of dry dose units include, for example, tablets, pared to administration of prodrug without inhibitor. capsules (e.g., Solid capsules, capsules containing liquid), 1102 Dose units find use in methods for increasing patient thin film, microparticles, granules, powder and the like. Dose compliance of a patient with a therapy prescribed by a clini units can be provided as liquid dose units, where the dose cian, where such methods involve directing administration of units can be provided as single or multiple doses of a formu a dose unit described herein to a patient in need of therapy so lation containing prodrug and inhibitor in liquid form. Single as to provide for increased patient compliance as compared to doses of a dry or liquid dose unit can be disposed within a a therapy involving administration of drug and/or as com sealed container, and sealed containers optionally provided in pared to administrations of prodrug without inhibitor. Such a packaging system, e.g., to provide for a prescribed number methods can help increase the likelihood that a clinician of doses, to provide for shipment of dose units, and the like. specified therapy occurs as prescribed. 1097 Dose units can be formulated such that the prodrug 1103 Dose units can provide for enhanced patient com and inhibitor are present in the same carrier, e.g., solubilized pliance and clinician control. For example, by limiting a PK or Suspended within the same matrix. Alternatively, dose parameter (e.g., Such as drug Cmax or drug exposure) when units can be composed of two or more portions, where the multiples (e.g., two or more, three or more, or four or more) prodrug and inhibitor can be provided in the same or different dose units are ingested, a patient requiring a higher dose of portions, and can be provided in adjacent or non-adjacent drug must seek the assistance of a clinician. The dose units portions. can provide for control of the degree to which a patient can 1098 Dose units can be provided in a container in which readily “self-medicate', and further can provide for the they are disposed, and may be provided as part of a packaging patient to adjust dose to a dose within a permissible range. system (optionally with instructions for use). For example, Dose units can provide for reduced side effects, by for dose units containing different amounts of prodrug can be example, providing for delivery of drug at an efficacious dose provided in separate containers, which containers can be dis but with a modified PK profile over a period of treatment, e.g., posed with in a larger container (e.g., to facilitate protection as defined by a decreased PK parameter (e.g., decreased drug of dose units for shipment). For example, one or more dose Cmax, decreased drug exposure). units as described herein can be provided in separate contain 1104 Dose units find use in methods to reduce the risk of ers, where dose units of different composition are provided in unintended overdose of drug that can follow ingestion of separate containers, and the separate containers disposed multiple doses taken at the same time or over a short period of within package for dispensing. time. Such methods of the present disclosure can provide for 1099. In another example, dose units can be provided in a reduction of risk of unintended overdose as compared to risk double-chambered dispenser where a first chamber contains a of unintended overdose of drug and/or as compared to risk of prodrug formulation and a second chamber contains an unintended overdose of prodrug without inhibitor. Such inhibitor formulation. The dispenser can be adapted to pro methods involve directing administration of a dosage vide for mixing of a prodrug formulation and an inhibitor described herein to a patient in need of drug released by formulation prior to ingestion. For example, the two cham conversion of the prodrug. Such methods can help avoid bers of the dispenser can be separated by a removable wall unintended overdosing due to intentional or unintentional (e.g., frangible wall) that is broken or removed prior to admin misuse of the dose unit. istration to allow mixing of the formulations of the two cham 1105 The present disclosure provides methods to reduce bers. The first and second chambers can terminate into a misuse and abuse of a drug, as well as to reduce risk of dispensing outlet, optionally through a common chamber. overdose, that can accompany ingestion of multiples of doses The formulations can be provided in dry or liquid form, or a of a drug, e.g., ingested at the same time. Such methods US 2014/O121 152 A1 May 1, 2014 67 generally involve combining in a dose unit a prodrug and an Synthesis of Ketone-Modified Opioid Prodrugs inhibitor of a GI enzyme that mediates release of drug from the prodrug, where the inhibitor is present in the dose unit in Example 1 an amount effective to attenuate release of drug from the prodrug, e.g., following ingestion of multiples of dose units Synthesis of oxycodone 6-(N-methyl-N-(2-amino) by a patient. Such methods provide for a modified concentra ethylcarbamate (Compound KC-19) tion-dose PK profile while providing therapeutically effective levels from a single dose unit, as directed by the prescribing 1109 clinician. Such methods can provide for, for example, reduc tion of risks that can accompany misuse and/or abuse of a prodrug, particularly where conversion of the prodrug pro vides for release of a narcotic or other drug of abuse (e.g., active agent). For example, when the prodrug provides for release of a drug of abuse, dose units can provide for reduc tion of reward that can follow ingestion of multiples of dose units of a drug of abuse. 1106 Dose units can provide clinicians with enhanced flexibility in prescribing drug. For example, a clinician can prescribe a dosage regimen involving different dose strengths, which can involve two or more different dose units of prodrug and inhibitor having different relative amounts of prodrug, different amounts of inhibitor, or different amounts of both prodrug and inhibitor. Such different strength dose units can provide for delivery of drug according to different PK parameters (e.g., drug exposure, drug Cmax, and the like as described herein). For example, a first dose unit can pro vide for delivery of a first dose of drug following ingestion, and a second dose unit can provide for delivery of a second dose of drug following ingestion. The first and second pro drug doses of the dose units can be different strengths, e.g., the second dose can be greater than the first dose. A clinician can thus prescribe a collection of two or more, or three or phosgene more dose units of different strengths, which can be accom panied by instructions to facilitate a degree of self-medica tion, e.g., to increase delivery of an active agent drug accord ing to a patient’s needs to treat pain. Thwarting Tampering by Trypsin Mediated Release of Active Agent from Prodrugs 1107 The disclosure provides for a composition compris ing a compound disclosed herein and a trypsin inhibitor that reduces drug abuse potential. A trypsin inhibitor can thwart the ability of a user to apply trypsin to effect the release of an active agent from the active agent prodrug in vitro. For example, if an abuser attempts to incubate trypsin with a composition of the embodiments that includes an active agent prodrug and a trypsin inhibitor, the trypsin inhibitor can reduce the action of the added trypsin, thereby thwarting attempts to release the active agent for purposes of abuse.

EXAMPLES 1108 The following examples are put forth so as to pro vide those of ordinary skill in the art with a complete disclo Sure and description of how to make and use the embodi Preparation of Compound A ments, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to 1110 2-(Aminoethyl)-methyl-carbamic acid benzyl ester represent that the experiments below are all or the only (2.0 g, 9.6 mmol) was dissolved in dichloroethene (DCE) (20 experiments performed. Efforts have been made to ensure mL) at room temperature. Triethyl amine (NEt) (1.40 mL. accuracy with respect to numbers used (e.g. amounts, tem 11.5 mmol) was added, followed by di-tert-butyl dicarbonate perature, etc.) but some experimental errors and deviations (BOCO) (10.5 g., 48 mmol) and dimethylaminopyridine should be accounted for. Unless indicated otherwise, parts are (DMAP) (120 mg). The reaction mixture was stirred at room parts by weight, molecular weight is weight average molecu temperature under nitrogen (N) for 2 hand then heated at 60° lar weight, temperature is in degrees Celsius, and pressure is C. for 16 h. The reaction mixture was then concentrated. The at or near atmospheric. Standard abbreviations may be used. residue was purified by Silica gel chromatography, using 4/1 US 2014/O121 152 A1 May 1, 2014

hexanes/EtOAc, to give Compound A in 86% yield (3.4g, 8.3 -continued mmol). MS: (m/z) calc: 408.2, observed (M+Na") 431.9. Preparation of Compound B 1111 Compound A (1.3 g, 3.18 mmol) was dissolved in methanol/EtOAc (10 mL/3 mL respectively). The mixture was degassed and saturated with N. Palladium on carbon (Pd/C) (330 mg, 5% on carbon) was added. The mixture was shaken in a Parr hydrogenator flask (50 psi H) for 4 h. The mixture was then filtered through a celite pad, and the filtrate was concentrated to give Compound B (1.08 g, yield exceeded quantitative). Compound B was used without fur ther purification. KC-19 Preparation of Compound C 1114. Oxycodone free base (6.5g, 20.6 mmol) was dis solved in dry, degassed tetrahydrofuran (120 mL), and the 1112 Compound B (500 mg, 1.82 mmol) and NEt (0.4 mixture was cooled to -10°C. using a dry ice/acetone bath. mL, 2.74 mmol) were mixed together in dichloromethane (4 Potassium bis(trimethylsilyl)amide (KHMDS) (103.0 mL, mL). The mixture was added to a pre-chilled 0°C. solution of 51.6 mmol, 0.5 M in toluene) was added via cannula. The phosgene (5.5 mL, 0.5 M in toluene). The reaction mixture mixture was stirred under N at below -5°C. for 30 min. was stirred at 0°C. for 1 h, followed by dilution with ether (20 N,N-Bis(tert-butyl) N'-2-(chlorocarbonyl(methyl)amino) mL) and filtration through filter paper. The filtrate was con ethylcarbamate (8.0 g, 23.7 mmol), (Compound C) in THF centrated and passed through a short silica gel column (10 (30 mL) was then added via cannula over 15 min. The mixture cmx3 cm), and eluted with 3/1 hexanes/EtOAc. The fractions was stirred at -5°C. for 30 min. Another portion of carbamoyl were concentrated to give N,N-Bis(tert-butyl) N'-2-(chloro chloride (4.0 g, 11.9 mmol) in THF (10 mL) was added. The carbonyl(methyl)amino)ethylcarbamate (Compound C) as a reaction was stirred at room temperature for 2 h. Sodium colorless solid in quantitative yield (615 mg, 1.82 mmol). bicarbonate (10 mL, sat. aq.) was added. The mixture was concentrated under vacuum to half of its initial volume. MS: (m/z) calc: 336.1, observed (M+Na") 359.8. EtOAc (50 mL) was added, and layers were separated. The Synthesis of Oxycodone 6-(N-methyl-N-(2-amino) organic phase was further washed with water (3x20 mL) and brine (40 mL), and then was concentrated. The residue was ethylcarbamate (Compound KC-19) purified by silica gel chromatography, using DCM/MeOH 1113 (gradient 100/1 to 100/15) to afforda white foam in 55% yield (7.0 g, 13.4 mmol). This material was dissolved in a 1:1 mixture of DCM/trifluoroacetic acid (TFA) (20 mL/20 mL) at 1. KHMDS: room temperature and stirred for 1 h. The solution was then concentrated under vacuum to afford a TFA salt of oxycodone 6-(N-methyl-N-(2-amino)ethylcarbamate (Compound O. O KC-19) as a thick oil (7.3 g, 11.4 mmol. 99% purity). MS: in (m/z) calc: 415.2, observed (M+H") 416.5. ----- Example 2 O Synthesis of N-1-2-(oxycodone-6-enol-carbonyl N / k methyl-amino)-ethylamine-L-arginine-malonate OH (Compound KC-3) also named: N-(S)-4-guani C dino-1-2-(methyl-(5R.9R,13S, 14S)-4,5a-epoxy-6, 2. TFADCM 7-didehydro-14-hydroxy-3-methoxy-17-methylmor phinan-6-oxycarbonyl-amino)-ethylcarbamoyl - O O O butyl-malonate 1115

He ACN, water

US 2014/O121 152 A1 May 1, 2014 70

-continued

KC-3

Preparation of Compound D DIEA (16.9 mL, 97.2 mmol) in DMF (150 mL) was cooled in an ice bath followed by the addition of a solution of HATU 1116. A solution of N-methylethylenediamine (27.0 g, (13.8 g. 36.4 mmol) dropwise over 20 min. The temperature 364 mmol) and ethyl trifluoroacetate (96.6 mL, 812 mmol) in of the reaction mixture was raised to ambient temperature, a mixture of ACN (350 mL) and water (7.8 mL, 436 mmol) and stirring was continued for an additional 1 h. The reaction was refluxed with stiffing overnight. Solvents were evapo mixture was diluted with EtOAc (1 L) and extracted with rated under vacuum. The residue was re-evaporated with water (3x200 mL) and brine (200 mL). The organic layer was i-PrCH (3x100 mL), followed by heat-cool crystallization dried over MgSO and evaporated to provide Compound G from DCM (500 mL). Formed crystals were filtered, washed (24.4g, yield exceeded quantitative) as a yellowish oil. LC with DCM and dried under vacuum to provide Compound D MS M+H 717.4 (CHNOS+H, calc: 717.9). Com (88.3 g, 85%) as white solid powder. pound G was used directly in the next reaction without puri Preparation of Compound E fication as a dioxane Solution. 1117. A solution of Compound D (88.2g, 311 mmol) and Preparation of Compound H DIEA (54.1 mL, 311 mmol) in THF (350 mL) was cooled in an ice bath, followed by the addition of a solution of N-(ben 1120 Compound G (24.4g, -30.4 mmol) was dissolved in Zyloxycarbonyl)succinimide (76.6 g. 307 mmol) in THF (150 dioxane (150 mL) and treated with 4 NHCl/dioxane (150 mL. mL) dropwise over the period of 20 min. The temperature of 600 mmol) at ambient temperature for 1 h. The solvent was the reaction mixture was raised to ambient temperature and then evaporated. The residue was suspended in i-ProH (100 stirring was continued for an additional 30 min. Solvents mL), and the mixture was evaporated (procedure was were then evaporated and the resulting residue was dissolved repeated twice). The residue was then dried under vacuum to in EtOAc (600 mL). The organic layer was extracted with 5% provide Compound H (21.1 g, yield exceeded quantitative) as aq. NaHCO (2x150 mL) and brine (150 mL). The organic a yellowish solid. LC-MS M+H 617.5 (CHNOS+H, layer was evaporated to provide Compound E as yellowish calc: 617.8). Compound H was used directly in the next oil. LC-MS M+H 305.1 (CHFNO+H, calc: 305.3). reaction without purification as a DMF solution. Compound E was used directly in the next reaction without purification as a MeOH solution. Preparation of Compound I Preparation of Compound F 1121. A solution of Compound H (21.1 g, ~30.4 mmol), 1118. To a solution of Compound E (-3.11 mmol) in mono-tert-butylmalonate (5.9 mL, 36.7 mmol), BOP (16.2g, MeOH (1.2 L) was added a solution of LiOH (14.9 g, 622 36.7 mmol) and DIEA (14.9 mL, 83.5 mmol) in DMF (100 mmol) in water (120 mL). The reaction mixture was stirred at mL) was maintained at ambient temperature for 1 h. The ambient temperature for 3 h. Solvents were evaporated to reaction mixture was diluted with EtOAc (1 L) and extracted 75% of the initial volume followed by dilution with water with water (500 mL), 5% aq. NaHCO, (500 mL), water (400 mL). The solution was extracted with EtOAc (2x300 (3x500 mL) and brine (500 mL). The organic layer was dried mL). The organic layer was washed with brine (200 mL), over MgSO filtered, and then evaporated to provide Com dried over MgSO and evaporated under vacuum. The residue pound I (24.5 g, 97%) as a yellowish amorphous solid. LC was dissolved in ether (300 mL) and treated with 2 NHCl/ MS M+H 759.6 (CHNOS+H, calc: 759.9). Com ether (200 mL). Formed precipitate was filtrated, washed with pound I was used without further purification. ether and dried under vacuum to provide the hydrochloric salt of Compound F (67.8 g. 89%) as a white solid. LC-MS Preparation of Compound J M+H 209.0 (CHNO+H, calc: 209.3). Compound F was used directly in the next reaction without purification as 1122 Compound I (12.3 g, 16.7 mmol) was dissolved in a DMF solution. methanol (100 mL) followed by the addition of a Pd/C (5% wt, 2.0 g) Suspension in water (2 mL). The reaction mixture Preparation of Compound G was subjected to hydrogenation (Parr apparatus, 70 psi H) at ambient temperature for 1 h. The catalyst was then filtered 1119. A solution of Boc-Arg(Pbf)-OH (16.0 g, -30.4 and washed with methanol. The filtrate was evaporated under mmol), Compound F hydrochloride (8.2g, 33.4 mmol), and vacuum to provide Compound J (10.0 g, 99%) as a colorless US 2014/O121 152 A1 May 1, 2014

amorphous solid. LC-MSM-I-H 625.5 (CHNO,S+H, Example 3 calc: 625.8). Compound J was used without further purifica tion. Synthesis of N-(oxycodone-6-enol-carbonyl)piperi dine-2-methylamine (Compound KC-11) and Preparation of Oxycodone Free Base N-(oxycodone-6-enol-carbonyl)piperidine-2-methy lamine-L-arginine-L-alanine-acetate (Compound 1123. Oxycodone hydrochloride (10.0g, 28.5 mmol) was KC-13) dissolved in chloroform (150 mL) and washed with 5% aq. NaHCO, (50 mL). The organic layer was dried over MgSO 1127 and evaporated. The residue was dried under vacuum over night to provide oxycodone free base (8.3g, 93%) as a white solid.

Preparation of Compound K 1124. A solution of oxycodone free base (6.6 g. 21.0 KHMDS; mmol) in THF (400 mL) was cooled to -20°C., followed by addition of a 0.5M solution of KHMDS intoluene (46.3 mL, 23.1 mmol). The obtained solution was then added to a solu tion of 4-nitro-phenyl chloroformate (4.3 g, 21.0 mmol) in THF (100 mL) dropwise over the period of 20 minat -20°C. The reaction was maintained at -20°C. for an additional 1 h, followed by addition of a solution of Compound J (10.0 g, 16.1 mmol) in THF (200 mL) at -20°C. The reaction mixture was allowed to warm to ambient temperature and stirred

overnight. Solvents were evaporated under vacuum. The resulting residue was dissolved in EtOAc (20 mL) and pre cipitated with ether (1 L). The formed precipitate was fil trated, washed with ether and dried under vacuum to provide Compound K (13.6 g., 87%) as an off-white solid. LC-MS M+H 966.9 (CH7NOS+H, calc: 966.2). Synthesis of N-1-2-(oxycodone-6-enol-carbonyl methyl-amino)-ethylamine-L-arginine-malonate (Compound KC-3) 1125 Compound K (13.6 g. 14.1 mmol) was dissolved in a mixture of 5% m-cresol/TFA (100 mL). The reaction mix ture was maintained at ambient temperature for 1 h, followed by dilution with ethyl ether (1 L). The formed precipitate was filtered, washed with ether and hexane, and dried under vacuum to provide a TFA salt of Compound KC-3 (11.4g, 81%) as an off-white solid. LC-MS M+H 658.6 (CHN.O+H, calc: 658.7). 1126. The TFA salt of crude Compound KC-3 (11.4g, 11.4 mmol) was dissolved in water (50 mL). The obtained Boc solution was subjected to HPLC purification. Nanosyn-Pack N HC Dioxane YMC-GEL-ODSA (100-10) C-18 column (75x500 mm); -e- flow rate: 250 mL/min: injection volume 50 mL. mobile phase A: 100% water, 0.1% TFA; mobile phase B: 100% ACN, 0.1% TFA: isocratic elution at 0% B in 4 min, gradient elution from 0% to 10% B in 20 min, isocratic elution at 10% B in 30 min, gradient elution from 10% B to 30% B in 41 min: detection at 254 nm. Fractions containing Compound KC-3 were combined and concentrated under vacuum. The TFA counterion of the latter was replaced with an HCl counterion via lyophilization using 0.1N HCl to provide an HCl salt of Compound KC-3 (4.2g, 41% yield) as a white solid. LC-MS M+H 658.6 (CHNO+H, calc: 658.7). US 2014/O121 152 A1 May 1, 2014 72

-continued -continued

O H N NH Ac2O, 2 DIEA O -es NH2 NH Boc-Arg(Pbf)-OH Ho- Pbf HATU, DIEA H--- H

O O KC-11 NS-S-NH : TFAf"R H cresol O Hess NH

N ls.N Pof O H H N NHBOc HCIf H Dioxane Her NH

N l N Pbf H H O E O N O N 1s O

O N NH2

NH2 Boc N Ala-OH HATU NH DIEA KC-13 N ls.N Pof H H Preparation of Oxycodone Free Base (L): 1128 Oxycodone-hydrochloride (21.0 g, 59.7 mmol) was P dissolved in water (250 mL). This solution was basified with saturated aqueous NaHCO (to pH 8-9) and extracted with DCM (3x250 mL). The combined organic layer was dried

over NaSO and filtered; removal of solvents under vacuum afforded Compound L in 98% yield (18.5g, 58.8 mmol) as a O white solid. LC-MSM--H 316.1 (C.HNO+H, calc:316. B OC Y HCIA 2). Compound L was used directly in the next reaction with N N Dioxane out further purification. He Preparation of Compound N 1129. To a solution of Compound L (14.71 g, 46.7 mmol) in THF (250 mL) at –60° C. was added 0.5 M KHMDS solution in THF (103 mL) dropwise. After stirring at-60° C. for 30 min, the reaction mixture was added to a solution of 4-nitrophenyl chloroformate at -60° C. (9.41 g, 46.7 mmol) in THF (200 mL). This reaction mixture was then stirred for 30 min at -60° C., followed by addition of piperidine-2-yl methylcarbamic acid tert-butyl ester, also referred to hereinas US 2014/O121 152 A1 May 1, 2014

(RS)-piperidine-2-yl-methylcarbamic acid tert-butyl ester, reaction mixture was raised to ambient temperature, and stiff (5.0g, 23.3 mmol) in portions. The reaction was allowed to ing was continued for an additional 1 h. DMF was removed warm to ambient temperature and then stirred for 18 h. The under vacuum. Next the reaction mixture was diluted with reaction was then concentrated under vacuum, and the resi EtOAc (100 mL), and washed with water (3x50 mL) and due diluted with EtOAc (500 mL). The mixture was then brine (50 mL). The organic layer was separated, dried over washed with water (2x250 mL) and brine (250 mL). The NaSO, and filtered. Removal of solvents under vacuum organic layer was separated, dried over NaSO4, and filtered. afforded crude Compound Q, yield exceeded quantitative, Removal of solvents under vacuum afforded crude Com pound N. Crude Compound N was purified by flash chroma (0.69 g, 0.66 mmol) as an off-white solid. LC-MS M--H tography using 100% EtOAc. Removal of solvent under 1035.6 (CHNOS+H, calc: 1035.5). Compound Q was vacuum afforded Compound N in 50% yield (6.5 g., 11.7 used directly in the next reaction without further purification. mmol) as a white solid. LC-MSM--H 556.1 (CHNO,+ H, calc: 555.3). Preparation of Compound R Preparation of N-(oxycodone-6-enol-carbonyl)pip 1134. A solution of Compound Q (0.69 g, 0.66 mmol) in eridine-2-methylamine) (KG-11) 1,4-dioxane (10 mL) was treated with hydrogen chloride (4.0 M solution in 1,4-dioxane, 10 mL). After 1 h, most of the 1130. A solution of Compound N (6.5 g, 11.7 mmol) in 1,4-dioxane was removed under vacuum until ~2 mL 1,4-dioxane (100 mL) was treated with hydrogen chloride remained. To this solution was added EtO (~100 mL). The (4.0M solution in 1,4-dioxane, 100 mL). After 1 h, most of the product precipitated as an HCl salt. The precipitate was 1,4-dioxane was removed under vacuum to ~20 mL remain washed with ether and dried under vacuum to afford crude ing. To this solution was added EtO (-750 mL). The product Compound R, yield exceeded quantitative, (0.67 g., 0.66 was then precipitated as an HCl salt. The precipitate was mmol) as an off-white solid. LC-MS M+H 935.8 filtered, washed with ether and dried under vacuum to afford (C2HNOS+H, calc: 935.5). Compound R was used Compound KC-11 in 97% yield (5.96 g, 11.3 mmol) as a directly in the next reaction without further purification. white solid. LC-MS IM+H 456.3 (CHNO+H, calc: 456.2). Compound KC-11 was used directly in the next reac tion without further purification. Preparation of Compound S Preparation of Compound O 1135 To a solution of Compound R (0.67 g., 0.66 mmol) and DIEA (0.37 mL, 2.1 mmol) in CHCl (50 mL) and cooled 1131) To a solution of Boc-Arg(Pbf)-OH (5.94 g, 11.3 to ~0° C., was added acetic anhydride (Ac2O) (0.07 mL, 0.7 mmol), Compound KC-11 (5.95 g, 11.3 mmol) and DIEA mmol). The reaction mixture was stirred at ambient tempera (8.24 mL, 47.4 mmol) in DMF (100 mL) at -0° C. was added ture for 30 min. The reaction mixture was diluted with CHCl HATU (4.28 g, 11.3 mmol) in portions over 10 min. The (50 mL), and washed with water (2x100 mL) and brine (50 temperature of the reaction mixture was raised to ambient mL). The organic layer was separated, dried over NaSO, temperature and stirring was continued for an additional 1 h. and filtered. Removal of solvents under vacuum afforded the DMF was removed under vacuum, and the reaction mixture crude CompoundS, yield exceeded quantitative, (0.65 g, 0.66 was diluted with EtOAc (300 mL), washed with water (3x150 mmol) as an off-white solid. LC-MS M+H 977.4 mL) and brine (150 mL). The organic layer was separated, (CHNOS+H, calc: 977.5). Compound S was used dried over NaSO, and filtered. Removal of solvents under vacuum afforded crude Compound O. This compound was directly in the next reaction without further purification. purified by silica gel chromatography using CHCl and 0% to 20% MeOH. Removal of solvents under vacuum afforded Preparation of N-(oxycodone-6-enol-carbonyl)pip Compound O in 23% yield (2.5g, 2.6 mmol) as a foamy solid. eridine-2-methylamine-L-arginine-L-alanine-acetate LC-MSM--H964.8 (CHNOS+H, calc: 964.5). (Compound KC-13) Preparation of Compound P 1136 Compound S (0.65 g, 0.66 mmol) was treated with 5% m-cresol in TFA (15 mL) for 1 h. The product was pre 1132 A solution of Compound O (2.5g, 2.6 mmol) in cipitated via addition of EtO (100 mL). The precipitate was 1,4-dioxane (50 mL) was treated with hydrogen chloride (4.0 washed with EtO (2x100 mL) and dried under vacuum to M solution in 1,4-dioxane, 50 mL). After 1 h, most of the afford crude Compound KC-13. This product was dissolved 1,4-dioxane was removed under vacuum until ~10 mL in water (15 mL), and the solution was subjected to HPLC remained. To this solution was added EtO (-500 mL). The purification. Nanosyn-Pack Microsorb (100-10) C-18 col product precipitated as an HCl salt. The precipitate was fil umn (50x300mm); flow rate: 100 mL/min: injection volume tered off, washed with ether, and dried under vacuum to afford 15 mL. mobile phase A: 100% water, 0.1% TFA; mobile Compound P in 52% yield (1.25 g, 1.33 mmol) as a white phase B: 100% ACN, 0.1%TFA: isocratic elution at 0% B in solid. LC-MSM-I-H 864.6 (CHN.OS+H, calc: 863.4). 5 min, gradient elution from 0% to 20% B in 20 min, isocratic Compound P was used directly in the next reaction without elution at 20% B in 20 min, gradient elution from 20% B to further purification. 45% B in 40 min; detection at 254 nm. Fractions containing Preparation of Compound Q the desired compound were combined and concentrated under vacuum. The residue was dissolved in ACN (-2 mL) 1133. To a solution of Boc-Ala-OH (0.13 g, 0.66 mmol), and 0.1 NHCl (-8 mL), and lyophilized overnight to provide Compound P (0.62g, 0.66 mmol), and DIEA (0.48 mL, 2.77 the hydrochloric salt of Compound KC-13 in 90% yield (0.65 mmol) in DMF (10 mL) at 5° C., was added HATU (0.25g, g, 0.59 mmol. 93.1% purity) as a white solid. LC-MSM-H 0.66 mmol) in portions over 5 min. The temperature of the 725.8 (CHNO+H, calc: 725.4).