US2010105914A1PendingUtilityA1
Caspase inhibitors and uses thereof
Est. expiryFeb 27, 2024(expired)· nominal 20-yr term from priority
Inventors:Jean-Damien CharrierSteven DurrantMichael MortimoreMichael O'DonnellAlistair RutherfordSharn RamayaJohn StudleyMartin TrudeauAdam Looker
A61P 9/04A61P 7/04A61P 9/00A61P 43/00A61P 9/10A61P 37/08A61P 9/08A61P 5/14A61P 37/06A61P 7/00A61P 37/00A61P 37/02A61P 3/10A61P 7/06A61P 31/18A61P 31/20A61P 31/00A61P 29/00A61P 31/04A61P 25/32A61P 27/02A61P 31/06A61P 35/02A61P 31/14A61P 25/00A61P 25/08A61P 25/14A61P 25/28A61P 35/00A61P 31/12A61P 25/16A61P 17/06A61P 17/02A61P 1/18A61P 1/00C07K 5/0202A61P 13/12A61P 21/04A61P 19/10A61P 17/00A61P 17/16A61P 17/04A61P 1/04A61P 21/00A61P 11/06A61P 11/00A61P 1/16A61P 11/16A61P 17/14A61P 21/02C07D 417/12C07D 417/06C07D 401/14A61P 19/08C07D 209/52A61P 19/00C07D 401/12A61K 38/06C07D 405/12A61P 19/02C07D 207/16C07D 409/14C07D 405/14Y02A50/30
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Claims
Abstract
The present invention provides a compound of formula I: wherein the variables are as defined herein. The present invention also provides processes for preparing the compounds of formula I, and intermediates thereof, pharmaceutical compositions comprising those compounds, and methods of using the compounds and compositions.
Claims
exact text as granted — not AI-modified1 - 36 . (canceled)
37 . A process for preparing a compound of formula I:
wherein Y is:
R 1 is H, C 1-12 aliphatic, C 3-10 cycloaliphatic, C 6-10 aryl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl, (C 3-10 cycloalkyl)-(C 1-12 aliphatic)-, cycloalkenyl-(C 1-12 aliphatic)-, (C 6-10 aryl)-(C 1-12 aliphatic)-, (5-10 membered heterocyclyl)-(C 1-12 aliphatic)-, or (5-10 membered heteroaryl)-(C 1-12 aliphatic)-, wherein any hydrogen atom is optionally and independently replaced by R 8 and any set of two hydrogen atoms bound to the same atom is optionally and independently replaced by carbonyl;
Ring A is:
wherein, in each ring, any hydrogen atom is optionally and independently replaced by R 4 and any set of two hydrogen atoms bound to the same atom is optionally and independently replaced by carbonyl;
when Ring A is
then
R is R 3 C(O)—, HC(O), R 3 SO 2 —, R 3 OC(O), (R 3 ) 2 NC(O), (R 3 )(H)NC(O), R 3 C(O)C(O)—, R 3 —, (R 3 ) 2 NC(O)C(O), (R 3 )(H)NC(O)C(O), or R 3 OC(O)C(O)—; and
R 3 is C 1-12 aliphatic, C 3-10 cycloaliphatic, C 6-10 aryl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl, (C 3-10 cycloaliphatic)-(C 1-12 aliphatic)-, (C 6-10 aryl)-(C 1-12 aliphatic)-, (5-10 membered heterocyclyl)-(C 1-12 aliphatic)-, or (5-10 membered heteroaryl)-(C 1-12 aliphatic)-; or two R 3 groups bound to the same atom form together with that atom a 3-10 membered aromatic or nonaromatic ring; wherein any ring is optionally fused to an C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, or 5-10 membered heterocyclyl; wherein up to 3 aliphatic carbon atoms may be replaced by a group selected from O, N, NR 9 , S, SO, and SO 2 , wherein R 3 is substituted with up to 6 substituents independently selected from R 8′ ;
when Ring A is
then
R is R 3 C(O)—, as shown in formula II,
and R 3 is phenyl, thiophene, or pyridine, wherein each ring is optionally substituted with up to 5 groups independently selected from R 8′ , and wherein at least one position on the phenyl, thiophene, or pyridine adjacent to bond x is substituted by R 12 , wherein R 12 has no more than 5 straight-chained atoms;
R 4 is halogen, —OR 9 , —NO 2 —CN —CF 3 , —OCF 1 , —R 9 , 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R 9 ) 2 , —SR 9 , —SOR 9 , —SO 2 R 9 —SO 2 N(R 9 ) 2 , —SO 3 R 9 , —C(O)R 9 , —C(O)C(O)R 9 , —C(O)C(O)OR 9 , —C(O)C(O)N(R 9 ) 2 , —C(O)CH 2 C(O)R 9 , —C(S)R 9 , —C(S)OR 9 , —C(O)OR 9 , —OC(O)R 9 , —C(O)N(R 9 ) 2 , —OC(O)N(R 9 ) 2 , —C(S)N(R 9 ) 2 , —(CH 2 ) 0-2 NHC(O)R 9 , —N(R 9 )N(R 9 )COR 9 , —N(R 9 )N(R 9 )C(O)OR 9 , —N(R 9 )N(R 9 )CON(R 9 ) 2 , —N(R 9 )SO 2 R 9 , —N(R 9 )SO 2 N(R 9 ) 2 , —N(R 9 )C(O)OR 9 , —N(R 9 )C(O)R 9 , —N(R 9 )C(S)R 9 , —N(R 9 )C(O)N(R 9 ) 2 , —N(R 9 )C(S)N(R 9 ) 2 —N(COR 9 )COR 9 , —N(OR 9 )R 9 , —C(═NH)N(R 9 ) 2 , —C(O)N(OR 9 )R 9 , —C(═NOR 9 )R 9 , —OP(O)(OR 9 ) 2 , —P(O)(R 9 ) 2 , —P(O)(OR 9 ) 2 , or —P(O)(H)(OR 9 );
R 2 is —C(R 5 )(R 6 )(R 7 ), C 6-10 aryl, 5-10 membered heteroaryl, or C 3-7 cycloalkyl;
R 5 is H or a C 1-6 straight-chained or branched alkyl;
R 6 is H or a C 1-6 straight-chained or branched alkyl;
R 7 is —CF 3 , —C 3-7 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, heterocycle, or a C 1-6 straight-chained or branched alkyl, wherein each carbon atom of the alkyl is optionally and independently substituted with R 10 ;
or R 5 and R 7 taken together with the carbon atom to which they are attached form a 3-10 membered cycloaliphatic;
R 8 and R 8′ are each independently halogen, —OR 9 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 9 , 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R 9 ) 2 , —SR 9 , —SOR 9 , —SO 2 R 9 , —SO 2 N(R 9 ) 2 —SO 3 R 9 , —C(O)R 9 , —C(O)C(O)R 9 , —C(O)C(O)OR 9 , —C(O)C(O)N(R 9 ) 2 , —C(O)CH 2 C(O)R 9 , —C(S)R 9 , —C(S)OR 9 , —C(O)OR 9 , —OC(O)R 9 , —C(O)N(R 9 ) 2 , —OC(O)N(R 9 ) 2 , —C(S)N(R 9 ) 2 , —(CH 2 ) 0-2 NHC(O)R 9 , —N(R 9 )N(R 9 )COR 9 , —N(R 9 )N(R 9 )C(O)OR 9 , —N(R 9 )N(R 9 )CON(R 9 ) 2 , —N(R 9 )SO 2 R 9 , —N(R 9 )SO 2 N(R 9 ) 2 , —N(R 9 )C(O)OR 9 , —N(R 9 )C(O)R 9 , —N(R 9 )C(S)R 9 , —N(R 9 )C(O)N(R 9 ) 2 , —N(R 9 )C(S)N(R 9 ) 2 , —N(COR 9 )COR 9 , —N(OR 9 )R 9 , —C(═NH)N(R 9 ) 2 , —C(O)N(OR 9 )R 9 , —C(═NOR 9 )R 9 , —OP(O)(OR 9 ) 2 , —P(O)(R 9 ) 2 , —P(O)(OR 9 ) 2 , and —P(O)(H)(OR 9 );
R 9 is hydrogen, C 1-12 aliphatic, C 3-10 cycloaliphatic, C 6-10 aryl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl, (C 3-10 cycloaliphatic)-(C 1-12 aliphatic)-, (C 6-10 aryl)-(C 1-12 aliphatic)-, (5-10 membered heterocyclyl)-(C 1-12 aliphatic)-, or heteroaryl-(C 1-12 aliphatic)-; wherein any hydrogen atom is optionally and independently replaced by R 13 and any set of two hydrogen atoms bound to the same atom is optionally and independently replaced by carbonyl;
R 10 is halogen, —OR 11 , —NO 2 , —CN, —CF 3 —OCF 3 , —R 11 , or —SR 11 ; wherein R 11 is C 1-4 -aliphatic-;
R 11 is C 1-4 -aliphatic-;
R 12 is halogen, —OR 11 , —NO 2 —CN —CF 3 —OCF 3 , —R 11 , or —SR 9 ;
R 13 is —OR 14 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 14 , 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R 14 ) 2 , —SR 14 , —SOR 14 , —SO 7 R 14 —SO 2 N(R 14 ) 2 —SO 3 R 14 , —C(O)R 14 , —C(O)C(O)R 14 , —C(O)C(O)OR 14 , —C(O)C(O)N(R 14 ) 2 , —C(O)CH 2 C(O)R 14 —C(S)R 14 , —C(S)OR 14 , —C(O)OR 14 , —OC(O)R 14 , —C(O)N(R 14 ) 2 , —OC(O)N(R 14 ) 2 , —C(S)N(R 14 ) 2 , —(CH 2 ) 0-2 NHC(O)R 14 , —N(R 14 )N(R 14 )COR 14 , —N(R 14 )N(R 14 )C(O)OR 14 , —N(R 14 )N(R 14 )CON(R 14 ) 2 , —N(R 14 )SO 2 R 14 , —N(R 14 )SO 2 N(R 14 ) 2 , —N(R 14 )C(O)OR 14 , —N(R 14 )C(O)R 14 , —N(R 14 )C(S)R 14 , —N(R 14 )C(O)N(R 14 ) 2 , —N(R 14 )C(S)N(R 14 ) 2 , —N(COR 14 )COR 14 , —N(OR 14 )R 14 , —C(═NH)N(R 14 ) 2 , —C(O)N(OR 14 )R 14 , —C(═NOR 14 )R 14 , —OP(O)(OR 14 ) 2 , —P(O)(R 14 ) 2 , —P(O)(OR 14 ) 2 , and —P(O)(H)(OR 14 );
R 14 is hydrogen, C 1-12 aliphatic, C 3-10 cycloaliphatic, C 6-10 aryl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl, (C 3-10 cycloaliphatic)-(C 1-12 aliphatic), (C 6-10 aryl)-(C 1-12 aliphatic)-, (5-10 membered heterocyclyl)-(C 1-12 aliphatic)-, or heteroaryl-(C 1-12 aliphatic)-;
comprising reacting a compound of formula 1:
wherein R 1 , R 2 , and Ring A are as defined above;
and a compound of formula RX, wherein R is as defined above and —X is OH or an appropriate derivative or leaving group, in the presence of conditions for coupling an amine and an acid (when X is OH) or appropriate acid derivative (when X is an appropriate leaving group) to provide the compound of formula I.
38 . A process for preparing a compound of formula I:
wherein Y is:
R 1 is H, C 1-12 aliphatic, C 3-10 cycloaliphatic, C 6-10 aryl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl, (C 3-10 cycloalkyl)-(C 1-12 aliphatic)-, cycloalkenyl-(C 1-12 aliphatic)-, (C 6-10 aryl)-(C 1-12 aliphatic)-, (5-10 membered heterocyclyl)-(C 1-12 aliphatic)-, or (5-10 membered heteroaryl)-(C 1-12 aliphatic)-, wherein any hydrogen atom is optionally and independently replaced by R 8 and any set of two hydrogen atoms bound to the same atom is optionally and independently replaced by carbonyl;
Ring A is:
wherein, in each ring, any hydrogen atom is optionally and independently replaced by R 4 and any set of two hydrogen atoms bound to the same atom is optionally and independently replaced by carbonyl;
when Ring A is
then
R is R 3 C(O)—, HC(O), R 3 SO 2 —, R 3 OC(O), (R 3 ) 2 NC(O), (R 3 )(H)NC(O), R 3 C(O)C(O)—, R 3 —, (R 3 ) 2 NC(O)C(O), (R 3 )(H)NC(O)C(O), or R 3 OC(O)C(O)—; and
R 3 is C 1-12 aliphatic, C 3-10 -cycloaliphatic, C 6-10 aryl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl, (C 3-10 cycloaliphatic)-(C 1-12 aliphatic)-, (C 6-10 aryl)-(C 1-12 aliphatic)-, (5-10 membered heterocyclyl)-(C 1-12 aliphatic)-, or (5-10 membered heteroaryl)-(C 1-12 aliphatic)-; or two R 3 groups bound to the same atom form together with that atom a 3-10 membered aromatic or nonaromatic ring; wherein any ring is optionally fused to an C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, or 5-10 membered heterocyclyl; wherein up to 3 aliphatic carbon atoms may be replaced by a group selected from O, N, NR 9 , S, SO, and SO 2 , wherein R 3 is substituted with up to 6 substituents independently selected from R 8′ ;
when Ring A is
then
R is R 3 C(O)—, as shown in formula II,
and R 3 is phenyl, thiophene, or pyridine, wherein each ring is optionally substituted with up to 5 groups independently selected from R 8′ , and wherein at least one position on the phenyl, thiophene, or pyridine adjacent to bond x is substituted by R 12 , wherein R 12 has no more than 5 straight-chained atoms;
R 4 is halogen, —OR 9 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 9 , 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R 9 ) 2 , —SR 9 , —SOR 9 , —SO 2 R 9 —SO 2 N(R 9 ) 2 , —SO 3 R 9 , —C(O)R 9 , —C(O)C(O)R 9 , —C(O)C(O)OR 9 , —C(O)C(O)N(R 9 ) 2 , —C(O)CH 2 C(O)R 9 , —C(S)R 9 , —C(S)OR 9 , —C(O)OR 9 , —OC(O)R 9 , —C(O)N(R 9 ) 2 , —OC(O)N(R 9 ) 2 , —C(S)N(R 9 ) 2 , —(CH 2 ) 0-2 NHC(O)R 9 , —N(R 9 )N(R 9 )COR 9 , —N(R 9 )N(R 9 )C(O)OR 9 , —N(R 9 )N(R 9 )CON(R 9 ) 2 , —N(R 9 )SO 2 R 9 , —N(R 9 )SO 2 N(R 9 ) 2 , —N(R 9 )C(O)OR 9 , —N(R 9 )C(O)R 9 , —N(R 9 )C(S)R 9 , —N(R 9 )C(O)N(R 9 ) 2 , —N(R 9 )C(S)N(R 9 ) 2 , —N(COR 9 )COR 9 , —N(OR 9 )R 9 , —C(═NH)N(R 9 ) 2 , —C(O)N(OR 9 )R 9 , —C(═NOR 9 )R 9 , —OP(O)(OR 9 ) 2 , —P(O)(R 9 ) 2 , —P(O)(OR 9 ) 2 , or —P(O)(H)(OR 9 );
R 2 is —C(R 5 )(R 6 )(R 7 ), C 6-10 aryl, 5-10 membered heteroaryl, or C 3-7 cycloalkyl;
R 5 is H or a C 1-6 straight-chained or branched alkyl;
R 6 is H or a C 1-6 straight-chained or branched alkyl;
R 7 is —CF 3 , —C 3-7 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, heterocycle, or a C 1-6 straight-chained or branched alkyl, wherein each carbon atom of the alkyl is optionally and independently substituted with R 10 ;
or R 5 and R 7 taken together with the carbon atom to which they are attached form a 3-10 membered cycloaliphatic;
R 8 and R 8′ are each independently halogen, —OR 9 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 9 , 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R 9 ) 2 , —SR 9 , —SOR 9 , —SO 2 R 9 , —SO 2 N(R 9 ) 2 , —SO 3 R 9 , —C(O)R 9 , —C(O)C(O)R 9 , —C(O)C(O)OR 9 , —C(O)C(O)N(R 9 ) 2 , —C(O)CH 2 C(O)R 9 , —C(S)R 9 , —C(S)OR 9 , —C(O)OR 9 , —OC(O)R 9 , —C(O)N(R 9 ) 2 , —OC(O)N(R 9 ) 2 , —C(S)N(R 9 ) 2 , —(CH 2 ) 0-2 NHC(O)R 9 , —N(R 9 )N(R 9 )COR 9 , —N(R 9 )N(R 9 )C(O)OR 9 , —N(R 9 )N(R 9 )CON(R 9 ) 2 , —N(R 9 )SO 2 R 9 , —N(R 9 )SO 2 N(R 9 ) 2 , —N(R 9 )C(O)OR 9 , —N(R 9 )C(O)R 9 , —N(R 9 )C(S)R 9 , —N(R 9 )C(O)N(R 9 ) 2 , —N(R 9 )C(S)N(R 9 ) 2 , —N(COR 9 )COR 9 , —N(OR 9 )R 9 , —C(═NH)N(R 9 ) 2 , —C(O)N(OR 9 )R 9 , —C(═NOR 9 )R 9 , —OP(O)(OR 9 ) 2 , —P(O)(R 9 ) 2 , —P(O)(OR 9 ) 2 and —P(O)(H)(OR 9 );
R 9 is hydrogen, C 1-12 aliphatic, C 3-10 cycloaliphatic, C 6-10 aryl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl, (C 3-10 cycloaliphatic)-(C 1-12 aliphatic)-, (C 6-10 aryl)-(C 1-12 aliphatic)-, (5-10 membered heterocyclyl)-(C 1-12 aliphatic)-, or heteroaryl-(C 1-12 aliphatic)-; wherein any hydrogen atom is optionally and independently replaced by R 13 and any set of two hydrogen atoms bound to the same atom is optionally and independently replaced by carbonyl;
R 12 is halogen, —OR 11 , —NO 2 , —CN, —CF 3 —OCF 3 , —R 11 , or —SR 11 ; wherein R 11 is C 1-4 -aliphatic-;
R 11 is C 1-4 -aliphatic-;
R 12 is halogen, —OR 11 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 11 , or —SR 9 ;
R 13 is —OR 14 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 14 , 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R 14 ) 2 , —SR 14 , —SOR 14 , —SO 2 R 14 —SO 2 N(R 14 ) 2 , —SO 3 R 14 , —C(O)R 14 , —C(O)C(O)R 14 , —C(O)C(O)OR 14 , —C(O)C(O)N(R 14 ) 2 , —C(O)CH 2 C(O)R 14 —C(S)R 14 , —C(S)OR 14 , —C(O)OR 14 , —OC(O)R 14 , —C(O)N(R 14 ) 2 , —OC(O)N(R 14 ) 2 , —C(S)N(R 14 ) 2 , —(CH 2 ) 0-2 NHC(O)R 14 , —N(R 14 )N(R 14 )COR 14 , —N(R 14 )N(R 14 )C(O)OR 14 , —N(R 14 )N(R 14 )CON(R 14 ) 2 , —N(R 14 )SO 2 R 14 , —N(R 14 )SO 2 N(R 14 ) 2 , —N(R 14 )C(O)OR 14 , —N(R 14 )C(O)R 14 , —N(R 14 )C(S)R 14 , —N(R 14 )C(O)N(R 14 ) 2 , —N(R 14 )C(S)N(R 14 ) 2 , —N(COR 14 )COR 14 , —N(OR 14 )R 14 , —C(═NH)N(R 14 ) 2 , —C(O)N(OR 14 )R 14 , —C(═NOR 14 )R 14 , —OP(O)(OR 14 ) 2 , —P(O)(R 14 ) 2 , —P(O)(OR 14 ) 2 , and —P(O)(H)(OR 14 );
R 14 is hydrogen, C 1-12 aliphatic, C 3-10 cycloaliphatic, C 6-10 aryl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl, (C 3-10 cycloaliphatic)-(C 1-12 aliphatic)-, (C 6-10 aryl)-(C 1-12 aliphatic)-, (5-10 membered heterocyclyl)-(C 1-12 aliphatic)-, or heteroaryl-(C 1-12 aliphatic)-;
comprising reacting a compound of formula 7-A:
wherein Ring A and R 1 are as defined above; and a compound of formula RNHCH(R 2 )C(O)X, wherein X is OH or an appropriate derivative or leaving group, in the presence of conditions for coupling an amine and an acid (when X is OH) or appropriate acid derivative (when X is not OH) to provide the compound of formula I.
39 . The process of claim 37 , further comprising the step of reacting the compound of formula I:
wherein Y is:
under hydrolysis conditions, to provide a compound of formula II
40 . A process for preparing a compound of formula 3-A:
wherein PG 1 is a suitable carboxylic acid protecting group;
PG 2 is a suitable nitrogen-protecting group;
Ring A is:
wherein, in each ring, any hydrogen atom is optionally and independently replaced by R 4 and any set of two hydrogen atoms bound to the same atom is optionally and independently replaced by carbonyl;
R 4 is halogen, —OR 9 , —NO 2 —CN —CF 3 , —OCF 1 , —R 9 , 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R 9 ) 2 , —SR 9 , —SOR 9 , —SO 2 R 9 —SO 2 N(R 9 ) 2 , —SO 3 R 9 , —C(O)R 9 , —C(O)C(O)R 9 , —C(O)C(O)OR 9 , —C(O)C(O)N(R 9 ) 2 , —C(O)CH 2 C(O)R 9 , —C(S)R 9 , —C(S)OR 9 , —C(O)OR 9 , —OC(O)R 9 , —C(O)N(R 9 ) 2 , —OC(O)N(R 9 ) 2 , —C(S)N(R 9 ) 2 , —(CH 2 ) 0-2 NHC(O)R 9 , —N(R 9 )N(R 9 )COR 9 , —N(R 9 )N(R 9 )C(O)OR 9 , —N(R 9 )N(R 9 )CON(R 9 ) 2 , —N(R 9 )SO 2 R 9 , —N(R 9 )SO 2 N(R 9 ) 2 , —N(R 9 )C(O)OR 9 , —N(R 9 )C(O)R 9 , —N(R 9 )C(S)R 9 , —N(R 9 )C(O)N(R 9 ) 2 , —N(R 9 )C(S)N(R 9 ) 2 , —N(COR 9 )COR 9 , —N(OR 9 )R 9 , —C(═NH)N(R 9 ) 2 , —C(O)N(OR 9 )R 9 , —C(═NOR 9 )R 9 , —OP(O)(OR 9 ) 2 , —P(O)(R 9 ) 2 , —P(O)(OR 9 ) 2 , or —P(O)(H)(OR 9 );
R 9 is hydrogen, C 1-12 aliphatic, C 3-10 cycloaliphatic, C 6-10 aryl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl, (C 3-10 cycloaliphatic)-(C 1-12 aliphatic)-, (C 6-10 aryl)-(C 1-12 aliphatic)-, (5-10 membered heterocyclyl)-(C 1-12 aliphatic), or heteroaryl-(C 1-12 aliphatic)-; wherein any hydrogen atom is optionally and independently replaced by R 13 and any set of two hydrogen atoms bound to the same atom is optionally and independently replaced by carbonyl; comprising:
reacting a compound of formula 2-A:
wherein PG 1 is as defined above;
and a compound of formula 20-A:
wherein PG 2 and Ring A are as defined above; X is OH or an appropriate leaving group, under conditions for coupling an amine and a carboxylic acid (when X is OH) or an amine and an appropriate carboxylic acid (when X is an appropriate leaving group) to provide the compound of formula 3-A.
41 . The process of claim 40 , wherein Ring A is
42 . The process of claim 40 , wherein Ring A is
43 . A compound selected from the following:
wherein
PG 1 is a suitable carboxylic acid protecting group;
PG 2 is a suitable nitrogen-protecting group;
Z is a Z-type protecting group;
R 1 is H, C 1-12 aliphatic, C 3-10 cycloaliphatic, C 6-10 aryl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl, (C 3-10 cycloalkyl)-(C 1-12 aliphatic)-, cycloalkenyl-(C 1-12 aliphatic)-, (C 6-10 aryl)-(C 1-12 aliphatic)-, (5-10 membered heterocyclyl)-(C 1-12 aliphatic)-, or (5-10 membered heteroaryl)-(C 1-12 aliphatic)-, wherein any hydrogen atom is optionally and independently replaced by R 8 and any set of two hydrogen atoms bound to the same atom is optionally and independently replaced by carbonyl;
Ring A is:
wherein, in each ring, any hydrogen atom is optionally and independently replaced by R 4 and any set of two hydrogen atoms bound to the same atom is optionally and independently replaced by carbonyl;
R 4 is halogen, —OR 9 , —NO 2 —CN, —CF 3 , —OCF 1 , —R 9 , 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R 9 ) 2 , —SR 9 , —SO 7 R 9 —SO 2 N(R 9 ) 2 , —SO 3 R 9 , —C(O)R 9 , —C(O)C(O)R 9 , —C(O)C(O)OR 9 , —C(O)C(O)N(R 9 ) 2 , —C(O)CH 2 C(O)R 9 , —C(S)R 9 , —C(S)OR 9 , —C(O)OR 9 , —OC(O)R 9 , —C(O)N(R 9 ) 2 , —OC(O)N(R 9 ) 2 , —C(S)N(R 9 ) 2 , —(CH 2 ) 0-2 NHC(O)R 9 , —N(R 9 )N(R 9 )COR 9 , —N(R 9 )N(R 9 )C(O)OR 9 , —N(R 9 )N(R 9 )CON(R 9 ) 2 , —N(R 9 )SO 2 R 9 , —N(R 9 )SO 2 N(R 9 ) 2 , —N(R 9 )C(O)OR 9 , —N(R 9 )C(O)R 9 , —N(R 9 )C(S)R 9 , —N(R 9 )C(O)N(R 9 ) 2 , —N(R 9 )C(S)N(R 9 ) 2 , —N(COR 9 )COR 9 , —N(OR 9 )R 9 , —C(═NH)N(R 9 ) 2 , —C(O)N(OR 9 )R 9 , —C(═NOR 9 )R 9 , —OP(O)(OR 9 ) 2 , —P(O)(R 9 ) 2 , —P(O)(OR 9 ) 2 , or —P(O)(H)(OR 9 );
R 9 is hydrogen, C 1-12 aliphatic, C 3-10 cycloaliphatic, C 6-10 aryl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl, (C 3-10 cycloaliphatic)-(C 1-12 aliphatic)-, (C 6-10 aryl)-(C 1-12 aliphatic)-, (5-10 membered heterocyclyl)-(C 1-12 aliphatic)-, or heteroaryl-(C 1-12 aliphatic)-; wherein any hydrogen atom is optionally and independently replaced by R 13 and any set of two hydrogen atoms bound to the same atom is optionally and independently replaced by carbonyl.
44 - 51 . (canceled)
52 . The process of claim 38 , further comprising the step of reacting the compound of
wherein Y is:
under hydrolysis conditions, to provide a compound of formula IIJoin the waitlist — get patent alerts
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